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Koo H, Park KC, Sohn HA, Kang M, Kim DJ, Park ZY, Park S, Min SH, Park SH, You YM, Han Y, Kim BK, Lee CH, Kim YS, Chung SJ, Yeom YI, Lee DC. Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development. Nat Commun 2025; 16:628. [PMID: 39819877 PMCID: PMC11739382 DOI: 10.1038/s41467-024-54476-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 11/12/2024] [Indexed: 01/19/2025] Open
Abstract
Cancers with activating mutations of KRAS show a high prevalence but remain intractable, requiring innovative strategies to overcome the poor targetability of KRAS. Here, we report that KRAS expression is post-translationally up-regulated through deubiquitination when the scaffolding function of NDRG3 (N-Myc downstream-regulated gene 3) promotes specific interaction between KRAS and a deubiquitinating enzyme, USP9X. In KRAS-mutant cancer cells KRAS protein expression, downstream signaling, and cell growth are highly dependent on NDRG3. In conditional KrasG12D knock-in mouse models of pancreatic ductal adenocarcinoma, Ndrg3 depletion abolishes Kras protein expression and suppresses intraepithelial neoplasia formation in pancreas. Mechanistically, KRAS protein binds to the C-terminal serine/threonine-rich region of NDRG3, subsequently going through deubiquitination by USP9X recruited to the complex. This interaction can be disrupted in a dominant-negative manner by a C-terminal NDRG3 fragment that binds KRAS but is defective in USP9X binding, highly suppressing KRAS protein expression and KRAS-driven cell growth. In summary, KRAS-driven cancer development critically depends on the deubiquitination of KRAS protein mediated by USP9X/NDRG3, and KRAS-addicted cancers could be effectively targeted by inhibiting the KRAS-NDRG3 interaction.
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Affiliation(s)
- Han Koo
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Kyung Chan Park
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Hyun Ahm Sohn
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Minho Kang
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Dong Joon Kim
- Department of Microbiology, College of Medicine, Dankook University, Cheonan, Chungcheongnam-do, Korea
- MRCRC, Dankook University, Cheonan, Chungcheongnam-do, Korea
| | - Zee-Yong Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Sehoon Park
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Sang Hyun Min
- Department of Innovative Pharmaceutical Sciences, Kyungpook National University, Deagu, Korea
| | - Seong-Hwan Park
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Yeon-Mi You
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Yohan Han
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Bo-Kyung Kim
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
| | - Chul-Ho Lee
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea
| | - Yeon-Soo Kim
- Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea
| | - Sang J Chung
- Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea
| | - Young Il Yeom
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea.
- College of Pharmacy, Chungnam National University, Daejeon, Korea.
| | - Dong Chul Lee
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon, Korea.
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Awan AB, Osman MJA, Khan OM. Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities. Cells 2025; 14:69. [PMID: 39851497 PMCID: PMC11763706 DOI: 10.3390/cells14020069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 01/26/2025] Open
Abstract
Ubiquitination is cells' second most abundant posttranslational protein modification after phosphorylation. The ubiquitin-proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials.
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Affiliation(s)
- Aiman B. Awan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
| | - Maryiam Jama Ali Osman
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
- Research Branch, Sidra Medicine, Doha P.O. Box 34110, Qatar
| | - Omar M. Khan
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar; (A.B.A.); (M.J.A.O.)
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Chen W, Shan Y, Wang M, Liang R, Sa R. Chicoric acid exerts therapeutic effects in DSS-induced ulcerative colitis by targeting the USP9X/IGF2BP2 axis. Br J Pharmacol 2024. [PMID: 39435543 DOI: 10.1111/bph.17354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 07/25/2024] [Accepted: 08/23/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND AND PURPOSE Chicoric acid, a hydroxycinnamic acid, exhibits anti-inflammation activities. However, the specific mechanisms underlying the effects of chicoric acid on dextran sulfate sodium (DSS)-induced colitis remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the protective effects of chicoric acid in DSS-induced colitis. EXPERIMENTAL APPROACH Mice with DSS-induced colitis (UC mice) were treated for a week with chicoric acid. Symptoms of colitis, colonic pathology, inflammation-related indicators, and intestinal mucosal barrier function were evaluated. RNA sequencing was performed on colon tissues to obtain differentially expressed genes. The deubiquitinating enzyme USP9X was selected, and the inhibitory and targeting effects of chicoric acid on USP9X were subsequently determined. In vivo and in vitro, DSS-induced colitis was treated with USP9X inhibitors WP1130 and EOAI3402143. Ubiquitination label-free quantitative proteomic analysis was performed to identify protein peptides that may undergo de-ubiquitination by USP9X. Co-immunoprecipitation (Co-IP), immunohistochemistry and western blotting were used to validate in vivo and in vitro results. KEY RESULTS Chicoric acid significantly alleviated clinical activity and histological changes, inhibited pro-inflammatory cytokine production and improved integrity of the intestinal barrier in UC mice. Moreover, chicoric acid suppressed USP9X expression in colonic tissues from UC mice. Furthermore, USP9X contributed to promoting the onset of UC and that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was deubiquitinated by USP9X. CONCLUSION AND IMPLICATIONS Chicoric acid ameliorated DSS-induced colitis by targeting the USP9X/IGF2BP2 axis, indicating that targeting the USP9X/IGF2BP2 axis presents a promising and innovative therapeutic approach for the treatment of UC.
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Affiliation(s)
- Wei Chen
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunan Shan
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Meng Wang
- Department of General Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Rui Liang
- Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ri Sa
- Department of Nuclear Medicine, The First Hospital of Jilin University, Changchun, China
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Ma M, Yi L, Pei Y, Zhang Q, Tong C, Zhao M, Chen Y, Zhu J, Zhang W, Yao F, Yang P, Zhang P. USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling. Nat Commun 2024; 15:7856. [PMID: 39251623 PMCID: PMC11385750 DOI: 10.1038/s41467-024-52201-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 08/29/2024] [Indexed: 09/11/2024] Open
Abstract
Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.
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Affiliation(s)
- Mengru Ma
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Lian Yi
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Yifei Pei
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Qimin Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Chao Tong
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Manyu Zhao
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Yuanhong Chen
- National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Jinghan Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fan Yao
- Hubei Hongshan Laboratory, College of Life Science and Technology, College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, China
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China
| | - Peijing Zhang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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Feng Q, Liu Q, Liu Z, Xu J, Yang Y, Zhu Y, Lu G, Xu G, Wu D, Wang F, Liu B, Wang W, Ding X. USP9X inhibits metastasis in pulmonary sarcomatoid carcinoma by regulating epithelial-mesenchymal transition, angiogenesis and immune infiltration. Transl Oncol 2024; 47:101950. [PMID: 38964032 PMCID: PMC11283126 DOI: 10.1016/j.tranon.2024.101950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/06/2024] [Accepted: 03/26/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Pulmonary sarcomatoid carcinoma (PSC) is a highly invasive pulmonary malignancy with an extremely poor prognosis. The results of previous studies suggest that ubiquitin-specific peptidase 9X (USP9X) contributes to the progression of numerous types of cancer. Nevertheless, there is little knowledge about the molecular mechanisms and functions of USP9X in the metastasis of PSC. METHODS Immunohistochemistry and western blotting were used to detect USP9X expression levels in PSC tissues and cells. Wound healing, transwell, enzyme-linked immunosorbent assay (ELISA), tube formation, and aortic ring assays were used to examine the function and mechanism of USP9X in the metastasis of PSC. RESULTS Expression of USP9X was markedly decreased and significantly correlated with metastasis and prognosis of patients with PSC. Then we revealed that USP9X protein levels were negatively associated with the levels of epithelial-mesenchymal transition (EMT) markers and the migration of PSC cells. It was confirmed that USP9X in PSC cells reduced VEGF secretion and inhibited tubule formation of human umbilical vein endothelial cells (HUVEC) in vitro. USP9X was detected to downregulate MMP9. Meanwhile, MMP9 was positively related to EMT, angiogenesis and was negatively related to immune infiltration in the public databases. USP9X was significantly negatively associated with the expression of MMP9, EMT markers, CD31, and positively associated with CD4, and CD8 in PSC tissues. CONCLUSION The present study reveals the vital role of USP9X in regulating EMT, angiogenesis and immune infiltration and inhibiting metastasis of PSC via downregulating MMP9, which provides a new effective therapeutic target for PSC.
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Affiliation(s)
- Qin Feng
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Qian Liu
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Zi Liu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Jianyu Xu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Yang Yang
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Ying Zhu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Guangxian Lu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Guangjuan Xu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Dan Wu
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Feng Wang
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Biao Liu
- Department of Pathology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
| | - Wenjuan Wang
- Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, China.
| | - Xinyuan Ding
- Medical Science and Technology Innovation Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Minicipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.
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Porreca V, Barbagallo C, Corbella E, Peres M, Stella M, Mignogna G, Maras B, Ragusa M, Mancone C. Unveil Intrahepatic Cholangiocarcinoma Heterogeneity through the Lens of Omics and Multi-Omics Approaches. Cancers (Basel) 2024; 16:2889. [PMID: 39199659 PMCID: PMC11352949 DOI: 10.3390/cancers16162889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/01/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is recognized worldwide as the second leading cause of morbidity and mortality among primary liver cancers, showing a continuously increasing incidence rate in recent years. iCCA aggressiveness is revealed through its rapid and silent intrahepatic expansion and spread through the lymphatic system leading to late diagnosis and poor prognoses. Multi-omics studies have aggregated information derived from single-omics data, providing a more comprehensive understanding of the phenomena being studied. These approaches are gradually becoming powerful tools for investigating the intricate pathobiology of iCCA, facilitating the correlation between molecular signature and phenotypic manifestation. Consequently, preliminary stratifications of iCCA patients have been proposed according to their "omics" features opening the possibility of identifying potential biomarkers for early diagnosis and developing new therapies based on personalized medicine (PM). The focus of this review is to provide new and advanced insight into the molecular pathobiology of the iCCA, starting from single- to the latest multi-omics approaches, paving the way for translating new basic research into therapeutic practices.
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Affiliation(s)
- Veronica Porreca
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Cristina Barbagallo
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Eleonora Corbella
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Marco Peres
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
| | - Michele Stella
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Giuseppina Mignogna
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Bruno Maras
- Department of Biochemistry Science, Sapienza University of Rome, 00185 Rome, Italy; (G.M.); (B.M.)
| | - Marco Ragusa
- Section of Biology and Genetics, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy; (C.B.); (M.S.); (M.R.)
| | - Carmine Mancone
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy; (E.C.); (M.P.)
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Xu W, Zhang Y, Su Y, Li L, Yang X, Wang L, Gao H. USP9X regulates the proliferation, survival, migration and invasion of gastric cancer cells by stabilizing MTH1. BMC Gastroenterol 2024; 24:239. [PMID: 39075342 PMCID: PMC11288101 DOI: 10.1186/s12876-024-03321-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 07/09/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND MutT homolog 1 (MTH1) sanitizes oxidized dNTP pools to promote the survival of cancer cells and its expression is frequently upregulated in cancers. Polyubiquitination stabilizes MTH1 to facilitate the proliferation of melanoma cells, suggesting the ubiquitin system controls the stability and function of MTH1. However, whether ubiquitination regulates MTH1 in gastric cancers has not been well defined. This study aims to investigate the interaction between MTH1 and a deubiquitinase, USP9X, in regulating the proliferation, survival, migration, and invasion of gastric cancer cells. METHODS The interaction between USP9X and MTH1 was evaluated by co-immunoprecipitation (co-IP) in HGC-27 gastric cancer cells. siRNAs were used to interfere with USP9X expression in gastric cancer cell lines HGC-27 and MKN-45. MTT assays were carried out to examine the proliferation, propidium iodide (PI) and 7-AAD staining assays were performed to assess the cell cycle, Annexin V/PI staining assays were conducted to examine the apoptosis, and transwell assays were used to determine the migration and invasion of control, USP9X-deficient, and USP9X-deficient plus MTH1-overexpressing HGC-27 and MKN-45 gastric cancer cells. RESULTS Co-IP data show that USP9X interacts with and deubiquitinates MTH1. Overexpression of USP9X elevates MTH1 protein level by downregulating its ubiquitination, while knockdown of USP9X has the opposite effect on MTH1. USP9X deficiency in HGC-27 and MKN-45 cells causes decreased proliferation, cell cycle arrest, extra apoptosis, and defective migration and invasion, which could be rescued by excessive MTH1. CONCLUSION USP9X interacts with and stabilizes MTH1 to promote the proliferation, survival, migration and invasion of gastric cancer cells.
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Affiliation(s)
- Wenji Xu
- Digestive System Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Yaping Zhang
- Central Laboratory, The Second Affiliated Hospital of Fujian Medical University, No. 34, Zhongshan North Road, Licheng District, Quanzhou, 362000, China
| | - Yingrui Su
- Nuclear Medicine Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Libin Li
- Digestive System Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Xinxia Yang
- Digestive System Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Lixing Wang
- Central Laboratory, The Second Affiliated Hospital of Fujian Medical University, No. 34, Zhongshan North Road, Licheng District, Quanzhou, 362000, China.
| | - Hongzhi Gao
- Central Laboratory, The Second Affiliated Hospital of Fujian Medical University, No. 34, Zhongshan North Road, Licheng District, Quanzhou, 362000, China.
- Neurosurgery Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China.
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Gao H, Chen Z, Zhao L, Ji C, Xing F. Cellular functions, molecular signalings and therapeutic applications: Translational potential of deubiquitylating enzyme USP9X as a drug target in cancer treatment. Biochim Biophys Acta Rev Cancer 2024; 1879:189099. [PMID: 38582329 DOI: 10.1016/j.bbcan.2024.189099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/13/2023] [Accepted: 03/31/2024] [Indexed: 04/08/2024]
Abstract
Protein ubiquitination, one of the most significant post-translational modifications, plays an important role in controlling the proteins activity in diverse cellular processes. The reversible process of protein ubiquitination, known as deubiquitination, has emerged as a critical mechanism for maintaining cellular homeostasis. The deubiquitinases (DUBs), which participate in deubiquitination process are increasingly recognized as potential candidates for drug discovery. Among these DUBs, ubiquitin-specific protease 9× (USP9X), a highly conserved member of the USP family, exhibits versatile functions in various cellular processes, including the regulation of cell cycle, protein endocytosis, apoptosis, cell polarity, immunological microenvironment, and stem cell characteristics. The dysregulation and abnormal activities of USP9X are influenced by intricate cellular signaling pathway crosstalk and upstream non-coding RNAs. The complex expression patterns and controversial clinical significance of USP9X in cancers suggest its potential as a prognostic biomarker. Furthermore, USP9X inhibitors has shown promising antitumor activity and holds the potential to overcome therapeutic resistance in preclinical models. However, a comprehensive summary of the role and molecular functions of USP9X in cancer progression is currently lacking. In this review, we provide a comprehensive delineation of USP9X participation in numerous critical cellular processes, complicated signaling pathways within the tumor microenvironment, and its potential translational applications to combat therapeutic resistance. By systematically summarizing the updated molecular mechanisms of USP9X in cancer biology, this review aims to contribute to the advancement of cancer therapeutics and provide essential insights for specialists and clinicians in the development of improved cancer treatment strategies.
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Affiliation(s)
- Hongli Gao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Liang Zhao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ce Ji
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Fei Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Yang W, Wang S, Tong S, Zhang WD, Qin JJ. Expanding the ubiquitin code in pancreatic cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166884. [PMID: 37704111 DOI: 10.1016/j.bbadis.2023.166884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/23/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
The ubiquitin-proteasome system (UPS) is a fundamental regulatory mechanism in cells, vital for maintaining cellular homeostasis, compiling signaling transduction, and determining cell fates. These biological processes require the coordinated signal cascades of UPS members, including ubiquitin ligases, ubiquitin-conjugating enzymes, deubiquitinases, and proteasomes, to ubiquitination and de-ubiquitination on substrates. Recent studies indicate that ubiquitination code rewriting is particularly prominent in pancreatic cancer. High frequency mutation or aberrant hyperexpression of UPS members dysregulates ferroptosis, tumor microenvironment, and metabolic rewiring processes and contribute to tumor growth, metastasis, immune evasion, and acquired drug resistance. We conduct an in-depth overview of ubiquitination process in pancreatic cancer, highlighting the role of ubiquitin code in tumor-promoting and tumor-suppressor pathways. Furthermore, we review current UPS modulators and analyze the potential of UPS modulators as cancer therapy.
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Affiliation(s)
- Wenyan Yang
- College of Pharmaceutical Science, Zhejiang University of Technology, Huzhou 313200, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Shiqun Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China
| | - Shengqiang Tong
- College of Pharmaceutical Science, Zhejiang University of Technology, Huzhou 313200, China
| | - Wei-Dong Zhang
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Jiang-Jiang Qin
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
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10
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Lv S, Zhang J, Peng X, Liu H, Liu Y, Wei F. Ubiquitin signaling in pancreatic ductal adenocarcinoma. Front Mol Biosci 2023; 10:1304639. [PMID: 38174069 PMCID: PMC10761520 DOI: 10.3389/fmolb.2023.1304639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 12/05/2023] [Indexed: 01/05/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor of the digestive system, characterized by rapid progression and being prone to metastasis. Few effective treatment options are available for PDAC, and its 5-year survival rate is less than 9%. Many cell biological and signaling events are involved in the development of PDAC, among which protein post-translational modifications (PTMs), such as ubiquitination, play crucial roles. Catalyzed mostly by a three-enzyme cascade, ubiquitination induces changes in protein activity mainly by altering their stability in PDAC. Due to their role in substrate recognition, E3 ubiquitin ligases (E3s) dictate the outcome of the modification. Ubiquitination can be reversed by deubiquitylases (DUBs), which, in return, modified proteins to their native form. Dysregulation of E3s or DUBs that disrupt protein homeostasis is involved in PDAC. Moreover, the ubiquitination system has been exploited to develop therapeutic strategies, such as proteolysis-targeting chimeras (PROTACs). In this review, we summarize recent progress in our understanding of the role of ubiquitination in the development of PDAC and offer perspectives in the design of new therapies against this highly challenging disease.
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Affiliation(s)
- Shengnan Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xinyu Peng
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huan Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yan Liu
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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11
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Riley AK, Grant M, Snell A, Vichas A, Moorthi S, Urisman A, Castel P, Wan L, Berger AH. The deubiquitinase USP9X regulates RIT1 protein abundance and oncogenic phenotypes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.30.569313. [PMID: 38077017 PMCID: PMC10705424 DOI: 10.1101/2023.11.30.569313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to EGFR tyrosine kinase inhibitors. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.
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Affiliation(s)
- Amanda K. Riley
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Molecular and Cellular Biology Program, University of Washington, Seattle, WA, USA
| | - Michael Grant
- Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Aidan Snell
- Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Athea Vichas
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Sitapriya Moorthi
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Anatoly Urisman
- Department of Pathology, University of California San Francisco, CA, USA
| | - Pau Castel
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA
| | - Lixin Wan
- Department of Molecular Oncology, Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Alice H. Berger
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Herbold Computational Biology Program, Public Health Science Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Lead contact:
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12
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Ren J, Yu P, Liu S, Li R, Niu X, Chen Y, Zhang Z, Zhou F, Zhang L. Deubiquitylating Enzymes in Cancer and Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303807. [PMID: 37888853 PMCID: PMC10754134 DOI: 10.1002/advs.202303807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/30/2023] [Indexed: 10/28/2023]
Abstract
Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.
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Affiliation(s)
- Jiang Ren
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Peng Yu
- Zhongshan Institute for Drug DiscoveryShanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP. R. China
| | - Sijia Liu
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceHangzhou310058China
| | - Ran Li
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Xin Niu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Yan Chen
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Zhenyu Zhang
- Department of NeurosurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450003P. R. China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Long Zhang
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
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13
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Meng Y, Hong C, Yang S, Qin Z, Yang L, Huang Y. Roles of USP9X in cellular functions and tumorigenesis (Review). Oncol Lett 2023; 26:506. [PMID: 37920433 PMCID: PMC10618932 DOI: 10.3892/ol.2023.14093] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/12/2023] [Indexed: 11/04/2023] Open
Abstract
Ubiquitin-specific peptidase 9X (USP9X) is involved in certain human diseases, including malignancies, atherosclerosis and certain diseases of the nervous system. USP9X promotes the deubiquitination and stabilization of diverse substrates, thereby exerting a versatile range of effects on pathological and physiological processes. USP9X serves vital roles in the processes of cell survival, invasion and migration in various types of cancer. The present review aims to highlight the current knowledge of USP9X in terms of its structure and the possible mediatory mechanisms involved in certain types of cancer, providing a thorough introduction to its biological functions in carcinogenesis and further outlining its oncogenic or suppressive properties in a diverse range of cancer types. Finally, several perspectives regarding USP9X-targeted pharmacological therapeutics in cancer development are discussed.
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Affiliation(s)
- Yimei Meng
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Chaojin Hong
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Sifu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Zhiquan Qin
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Liu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
| | - Yumei Huang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China
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14
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Song N, Deng L, Zeng L, He L, Liu C, Liu L, Fu R. USP9X deubiquitinates and stabilizes CDC123 to promote breast carcinogenesis through regulating cell cycle. Mol Carcinog 2023; 62:1487-1503. [PMID: 37314216 DOI: 10.1002/mc.23591] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023]
Abstract
Cell division cycle 123 (CDC123) has been implicated in a variety of human diseases. However, it remains unclear whether CDC123 plays a role in tumorigenesis and how its abundance is regulated. In this study, we found that CDC123 was highly expressed in breast cancer cells, and its high expression was positively correlated with a poor prognosis. Knowndown of CDC123 impaired the proliferation of breast cancer cells. Mechanistically, we identified a deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), that could physically interact with and deubiquitinate K48-linked ubiquitinated CDC123 at the K308 site. Therefore, the expression of CDC123 was positively correlated with USP9X in breast cancer cells. In addition, we found that deletion of either USP9X or CDC123 led to altered expression of cell cycle-related genes and resulted in the accumulation of cells population in the G0/G1 phase, thereby suppressing cell proliferation. Treatment with the deubiquitinase inhibitor of USP9X, WP1130 (Degrasyn, a small molecule compound that USP9X deubiquitinase inhibitor), also led to the accumulation of breast cancer cells in the G0/G1 phase, but this effect could be rescued by overexpression of CDC123. Furthermore, our study revealed that the USP9X/CDC123 axis promotes the occurrence and development of breast cancer through regulating the cell cycle, and suggests that it may be a potential target for breast cancer intervention. In conclusion, our study demonstrates that USP9X is a key regulator of CDC123, providing a novel pathway for the maintenance of CDC123 abundance in cells, and supports USP9X/CDC123 as a potential target for breast cancer intervention through regulating the cell cycle.
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Affiliation(s)
- Nan Song
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Ling Deng
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Lijie Zeng
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Li He
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Chunyan Liu
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Ling Liu
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
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15
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Neff RA, Bosch-Gutierrez A, Sun Y, Katsyv I, Song WM, Wang M, Walsh MJ, Zhang B. Dysfunction of ubiquitin protein ligase MYCBP2 leads to cell resilience in human breast cancers. NAR Cancer 2023; 5:zcad036. [PMID: 37435531 PMCID: PMC10331931 DOI: 10.1093/narcan/zcad036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/26/2023] [Indexed: 07/13/2023] Open
Abstract
Breast cancer is the most common type of cancer among women worldwide, and it is estimated that 294 000 new diagnoses and 37 000 deaths will occur each year in the United States alone by 2030. Large-scale genomic studies have identified a number of genetic loci with alterations in breast cancer. However, identification of the genes that are critical for tumorgenicity still remains a challenge. Here, we perform a comprehensive functional multi-omics analysis of somatic mutations in breast cancer and identify previously unknown key regulators of breast cancer tumorgenicity. We identify dysregulation of MYCBP2, an E3 ubiquitin ligase and an upstream regulator of mTOR signaling, is accompanied with decreased disease-free survival. We validate MYCBP2 as a key target through depletion siRNA using in vitro apoptosis assays in MCF10A, MCF7 and T47D cells. We demonstrate that MYCBP2 loss is associated with resistance to apoptosis from cisplatin-induced DNA damage and cell cycle changes, and that CHEK1 inhibition can modulate MYCBP2 activity and caspase cleavage. Furthermore, we show that MYCBP2 knockdown is associated with transcriptomic responses in TSC2 and in apoptosis genes and interleukins. Therefore, we show that MYCBP2 is an important genetic target that represents a key node regulating multiple molecular pathways in breast cancer corresponding with apparent drug resistance in our study.
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Affiliation(s)
- Ryan A Neff
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Almudena Bosch-Gutierrez
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- The Mount Sinai Center for RNA Biology and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yifei Sun
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- The Mount Sinai Center for RNA Biology and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Igor Katsyv
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Won-min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Martin J Walsh
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- The Mount Sinai Center for RNA Biology and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
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16
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Sisoudiya SD, Mishra P, Li H, Schraw JM, Scheurer ME, Salvi S, Doddapaneni H, Muzny D, Mitchell D, Taylor O, Sabo A, Lupo PJ, Plon SE. Identification of USP9X as a leukemia susceptibility gene. Blood Adv 2023; 7:4563-4575. [PMID: 37289514 PMCID: PMC10425687 DOI: 10.1182/bloodadvances.2023009814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 05/03/2023] [Accepted: 05/18/2023] [Indexed: 06/10/2023] Open
Abstract
We recently reported that children with multiple birth defects have a significantly higher risk of childhood cancer. We performed whole-genome sequencing on a cohort of probands from this study with birth defects and cancer and their parents. Structural variant analysis identified a novel 5 kb de novo heterozygous inframe deletion overlapping the catalytic domain of USP9X in a female proband with multiple birth defects, developmental delay, and B-cell acute lymphoblastic leukemia (B-ALL). Her phenotype was consistent with female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including previously reported female probands (n = 42) demonstrated that MRXS99F probands with B-ALL (n = 3) clustered with subjects with loss-of-function (LoF) USP9X variants and multiple anomalies. The cumulative incidence of B-ALL among these female probands (7.1%) was significantly higher than an age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology, and End Results database (P < .0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. In contrast, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females, and expression levels are comparable in leukemia samples from both sexes (P = .54), with the highest expressors being female patients with extra copies of the X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes, with low expression associated with poorer survival in patients with high-risk B-ALL.
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Affiliation(s)
- Saumya Dushyant Sisoudiya
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Pamela Mishra
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - He Li
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Jeremy M. Schraw
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Michael E. Scheurer
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Sejal Salvi
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | | | - Donna Muzny
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Danielle Mitchell
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Olga Taylor
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Aniko Sabo
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
| | - Philip J. Lupo
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
| | - Sharon E. Plon
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX
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17
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Cao F, Jiang Y, Chang L, Du H, Chang D, Pan C, Huang X, Yu D, Zhang M, Fan Y, Bian X, Li K. High-throughput functional screen identifies YWHAZ as a key regulator of pancreatic cancer metastasis. Cell Death Dis 2023; 14:431. [PMID: 37452033 PMCID: PMC10349114 DOI: 10.1038/s41419-023-05951-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 06/27/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023]
Abstract
Pancreatic cancer is a leading cause of cancer death due to its early metastasis and limited response to the current therapies. Metastasis is a complicated multistep process, which is determined by complex genetic alterations. Despite the identification of many metastasis-related genes, distinguishing the drivers from numerous passengers and establishing the causality in cancer pathophysiology remains challenging. Here, we established a high-throughput and piggyBac transposon-based genetic screening platform, which enables either reduced or increased expression of chromosomal genes near the incorporation site of the gene search vector cassette that contains a doxycycline-regulated promoter. Using this strategy, we identified YWHAZ as a key regulator of pancreatic cancer metastasis. We demonstrated that functional activation of Ywhaz by the gene search vector led to enhanced metastatic capability in mouse pancreatic cancer cells. The metastasis-promoting role of YWHAZ was further validated in human pancreatic cancer cells. Overexpression of YWHAZ resulted in more aggressive metastatic phenotypes in vitro and a shorter survival rate in vivo by modulating epithelial-to-mesenchymal transition. Hence, our study established a high-throughput screening method to investigate the functional relevance of novel genes and validated YWHAZ as a key regulator of pancreatic cancer metastasis.
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Affiliation(s)
- Fang Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yunpeng Jiang
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Chang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Beijing, China
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Hongzhen Du
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - De Chang
- Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Chunxiao Pan
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Xiaozheng Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Donglin Yu
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Mi Zhang
- Department of Pulmonary and Critical Care Medicine, 7th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yongna Fan
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China
| | - Xiaocui Bian
- Department of Pathology, Cell Resource Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, China.
| | - Kailong Li
- Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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18
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Tang YJ, Shuldiner EG, Karmakar S, Winslow MM. High-Throughput Identification, Modeling, and Analysis of Cancer Driver Genes In Vivo. Cold Spring Harb Perspect Med 2023; 13:a041382. [PMID: 37277208 PMCID: PMC10317066 DOI: 10.1101/cshperspect.a041382] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The vast number of genomic and molecular alterations in cancer pose a substantial challenge to uncovering the mechanisms of tumorigenesis and identifying therapeutic targets. High-throughput functional genomic methods in genetically engineered mouse models allow for rapid and systematic investigation of cancer driver genes. In this review, we discuss the basic concepts and tools for multiplexed investigation of functionally important cancer genes in vivo using autochthonous cancer models. Furthermore, we highlight emerging technical advances in the field, potential opportunities for future investigation, and outline a vision for integrating multiplexed genetic perturbations with detailed molecular analyses to advance our understanding of the genetic and molecular basis of cancer.
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Affiliation(s)
- Yuning J Tang
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Emily G Shuldiner
- Department of Biology, Stanford University, Stanford, California 94305, USA
| | - Saswati Karmakar
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Monte M Winslow
- Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
- Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
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19
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Coleman JC, Hallett SR, Grigoriadis AE, Conte MR. LARP4A and LARP4B in cancer: The new kids on the block. Int J Biochem Cell Biol 2023; 161:106441. [PMID: 37356415 DOI: 10.1016/j.biocel.2023.106441] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/09/2023] [Accepted: 06/17/2023] [Indexed: 06/27/2023]
Abstract
Recent developments have mounted a stunning body of evidence underlying the importance of RNA binding proteins (RBPs) in cancer research. In this minireview we focus on LARP4A and LARP4B, two paralogs belonging to the superfamily of La-related proteins, and provide a critical overview of current research, including their roles in cancer pathogenesis and cell proliferation, migration, cell cycle and apoptosis. We highlight current controversies surrounding LARP4A and LARP4B and conclude that their complex roles in tumorigenesis are cell-, tissue- and context-dependent, warning that caution must be exercised before categorising either protein as an oncoprotein or tumour-suppressor. We also reveal that LARP4A and LARP4B have often been confused with one another, adding uncertainty in delineating their functions. We suggest that further functional and mechanistic studies of LARP4 proteins present significant challenges for future investigations to recognise the vital contributions of these RBPs in cancer research.
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Affiliation(s)
- Jennifer C Coleman
- Centre for Craniofacial & Regenerative Biology, King's College London, London SE1 9RT, UK
| | - Sadie R Hallett
- Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK
| | | | - Maria R Conte
- Randall Centre for Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
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20
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Zheng X, Du Y, Liu M, Wang C. ITGA3 acts as a purity-independent biomarker of both immunotherapy and chemotherapy resistance in pancreatic cancer: bioinformatics and experimental analysis. Funct Integr Genomics 2023; 23:196. [PMID: 37270717 PMCID: PMC10239741 DOI: 10.1007/s10142-023-01122-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/05/2023]
Abstract
Contribution of integrin superfamily genes to treatment resistance remains uncertain. Genome patterns of thirty integrin superfamily genes were analyzed of using bulk and single-cell RNA sequencing, mutation, copy number, methylation, clinical information, immune cell infiltration, and drug sensitivity data. To select the integrins that are most strongly associated with treatment resistance in pancreatic cancer, a purity-independent RNA regulation network including integrins were constructed using machine learning. The integrin superfamily genes exhibit extensive dysregulated expression, genome alterations, epigenetic modifications, immune cell infiltration, and drug sensitivity, as evidenced by multi-omics data. However, their heterogeneity varies among different cancers. After constructing a three-gene (TMEM80, EIF4EBP1, and ITGA3) purity-independent Cox regression model using machine learning, ITGA3 was identified as a critical integrin subunit gene in pancreatic cancer. ITGA3 is involved in the molecular transformation from the classical to the basal subtype in pancreatic cancer. Elevated ITGA3 expression correlated with a malignant phenotype characterized by higher PD-L1 expression and reduced CD8+ T cell infiltration, resulting in unfavorable outcomes in patients receiving either chemotherapy or immunotherapy. Our findings suggest that ITGA3 is an important integrin in pancreatic cancer, contributing to chemotherapy resistance and immune checkpoint blockade therapy resistance.
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Affiliation(s)
- Xiaohao Zheng
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yongxing Du
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Mingyang Liu
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- Department of General Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, China.
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21
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Zhao T, Zhu G, Dubey HV, Flaherty P. Identification of significant gene expression changes in multiple perturbation experiments using knockoffs. Brief Bioinform 2023; 24:bbad084. [PMID: 36892174 PMCID: PMC10025447 DOI: 10.1093/bib/bbad084] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/20/2023] [Accepted: 02/13/2023] [Indexed: 03/10/2023] Open
Abstract
Large-scale multiple perturbation experiments have the potential to reveal a more detailed understanding of the molecular pathways that respond to genetic and environmental changes. A key question in these studies is which gene expression changes are important for the response to the perturbation. This problem is challenging because (i) the functional form of the nonlinear relationship between gene expression and the perturbation is unknown and (ii) identification of the most important genes is a high-dimensional variable selection problem. To deal with these challenges, we present here a method based on the model-X knockoffs framework and Deep Neural Networks to identify significant gene expression changes in multiple perturbation experiments. This approach makes no assumptions on the functional form of the dependence between the responses and the perturbations and it enjoys finite sample false discovery rate control for the selected set of important gene expression responses. We apply this approach to the Library of Integrated Network-Based Cellular Signature data sets which is a National Institutes of Health Common Fund program that catalogs how human cells globally respond to chemical, genetic and disease perturbations. We identified important genes whose expression is directly modulated in response to perturbation with anthracycline, vorinostat, trichostatin-a, geldanamycin and sirolimus. We compare the set of important genes that respond to these small molecules to identify co-responsive pathways. Identification of which genes respond to specific perturbation stressors can provide better understanding of the underlying mechanisms of disease and advance the identification of new drug targets.
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Affiliation(s)
- Tingting Zhao
- Department of Information Systems and Analytics, College of Business, Bryant University, Smithfield, 02917, RI, USA
- Center for Health and Behavioral Sciences, Bryant University, Smithfield, 02917, RI, USA
| | - Guangyu Zhu
- Department of Computer Science and Statistics, University of Rhode Island, Kingston, 02881, RI, USA
| | - Harsh Vardhan Dubey
- Department of Mathematics & Statistics, University of Massachusetts Amherst, Amherst, 01003, MA, USA
| | - Patrick Flaherty
- Department of Mathematics & Statistics, University of Massachusetts Amherst, Amherst, 01003, MA, USA
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22
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de Andrés MP, Jackson RJ, Felipe I, Zagorac S, Pilarsky C, Schlitter AM, Martinez de Villareal J, Jang GH, Costello E, Gallinger S, Ghaneh P, Greenhalf W, Knösel T, Palmer DH, Ruemmele P, Weichert W, Buechler M, Hackert T, Neoptolemos JP, Notta F, Malats N, Martinelli P, Real FX. GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma. Gut 2023; 72:535-548. [PMID: 36109153 DOI: 10.1136/gutjnl-2021-325803] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 08/05/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE GATA6 is a key regulator of the classical phenotype in pancreatic ductal adenocarcinoma (PDAC). Low GATA6 expression associates with poor patient outcome. GATA4 is the second most expressed GATA factor in the pancreas. We assessed whether, and how, GATA4 contributes to PDAC phenotype and analysed the association of expression with outcome and response to chemotherapy. DESIGN We analysed PDAC transcriptomic data, stratifying cases according to GATA4 and GATA6 expression and identified differentially expressed genes and pathways. The genome-wide distribution of GATA4 was assessed, as well as the effects of GATA4 knockdown. A multicentre tissue microarray study to assess GATA4 and GATA6 expression in samples (n=745) from patients with resectable was performed. GATA4 and GATA6 levels were dichotomised into high/low categorical variables; association with outcome was assessed using univariable and multivariable Cox regression models. RESULTS GATA4 messenger RNA is enriched in classical, compared with basal-like tumours. We classified samples in 4 groups as high/low for GATA4 and GATA6. Reduced expression of GATA4 had a minor transcriptional impact but low expression of GATA4 enhanced the effects of GATA6 low expression. GATA4 and GATA6 display a partially overlapping genome-wide distribution, mainly at promoters. Reduced expression of both proteins in tumours was associated with the worst patient survival. GATA4 and GATA6 expression significantly decreased in metastases and negatively correlated with basal markers. CONCLUSIONS GATA4 and GATA6 cooperate to maintain the classical phenotype. Our findings provide compelling rationale to assess their expression as biomarkers of poor prognosis and therapeutic response.
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Affiliation(s)
- Mónica P de Andrés
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Richard J Jackson
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Irene Felipe
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Sladjana Zagorac
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | | | - Anna Melissa Schlitter
- Institute of Pathology, School of Medicine, Technische Universitat Munchen, Munchen, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jaime Martinez de Villareal
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
- CIBERONC, Madrid, Spain
| | - Gun Ho Jang
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Steve Gallinger
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University, Toronto, Ontario, Canada
- Health Network, Toronto, Ontario, Canada
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada
| | - Paula Ghaneh
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Thomas Knösel
- Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Daniel H Palmer
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Petra Ruemmele
- Pathologisches Institute, Erlangen University Hospital, Erlangen, Germany
| | - Wilko Weichert
- Institute of Pathology, School of Medicine, Technische Universitat Munchen, Munchen, Germany
| | - Markus Buechler
- Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Thilo Hackert
- Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - John P Neoptolemos
- Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Faiyaz Notta
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Núria Malats
- CIBERONC, Madrid, Spain
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain
| | - Paola Martinelli
- Institute of Cancer Research, Clinic for Internal Medicine I, Medical University of Vienna, Vienna, Austria
| | - Francisco X Real
- Departament de Medicina i Ciències de la Vida, Universitt Pompeu Fabra, Barcelona, Spain
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23
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Hartl L, Roelofs JJTH, Dijk F, Bijlsma MF, Duitman J, Spek CA. C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC. Int J Mol Sci 2023; 24:ijms24021537. [PMID: 36675048 PMCID: PMC9867044 DOI: 10.3390/ijms24021537] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/14/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPβ or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan-Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPβ and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPβ as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPβ and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBβ and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.
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Affiliation(s)
- Leonie Hartl
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
| | - Joris J. T. H. Roelofs
- Department of Pathology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Frederike Dijk
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
- Department of Pathology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
| | - JanWillem Duitman
- Department of Pulmonary Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Amsterdam Infection & Immunity, Inflammatory Diseases, 1105 AZ Amsterdam, The Netherlands
| | - C. Arnold Spek
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands
- Correspondence:
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24
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Wang Y, Liu X, Huang W, Liang J, Chen Y. The intricate interplay between HIFs, ROS, and the ubiquitin system in the tumor hypoxic microenvironment. Pharmacol Ther 2022; 240:108303. [PMID: 36328089 DOI: 10.1016/j.pharmthera.2022.108303] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/16/2022] [Accepted: 10/26/2022] [Indexed: 11/09/2022]
Abstract
Alterations in protein ubiquitination and hypoxia-inducible factor (HIF) signaling both contribute to tumorigenesis and tumor progression. Ubiquitination is a dynamic process that is coordinately regulated by E3 ligases and deubiquitinases (DUBs), which have emerged as attractive therapeutic targets. HIF expression and transcriptional activity are usually increased in tumors, leading to poor clinical outcomes. Reactive oxygen species (ROS) are upregulated in tumors and have multiple effects on HIF signaling and the ubiquitin system. A growing body of evidence has shown that multiple E3 ligases and UBDs function synergistically to control the expression and activity of HIF, thereby allowing cancer cells to cope with the hypoxic microenvironment. Conversely, several E3 ligases and DUBs are regulated by hypoxia and/or HIF signaling. Hypoxia also induces ROS production, which in turn modulates the stability or activity of HIF, E3 ligases, and DUBs. Understanding the complex networks between E3 ligase, DUBs, ROS, and HIF will provide insights into the fundamental mechanism of the cellular response to hypoxia and help identify novel molecular targets for cancer treatment. We review the current knowledge on the comprehensive relationship between E3 ligase, DUBs, ROS, and HIF signaling, with a particular focus on the use of E3 ligase or DUB inhibitors in cancer.
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Affiliation(s)
- Yijie Wang
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China
| | - Xiong Liu
- School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Weixiao Huang
- School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China
| | - Junjie Liang
- The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China.
| | - Yan Chen
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, Shandong 250014, China; School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
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25
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LIU J, LEUNG CT, LIANG L, WANG Y, CHEN J, LAI KP, TSE WKF. Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis. Cancers (Basel) 2022; 14:cancers14143547. [PMID: 35884607 PMCID: PMC9323628 DOI: 10.3390/cancers14143547] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/24/2022] Open
Abstract
Simple Summary This review summarizes the current DUBs findings that correlate with the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The DUBs were further classified by their biological functions in terms of proliferation, metastasis, and apoptosis. The work provides an updated of the current findings, and could be used as a quick guide for researchers to identify target DUBs in cancers. Abstract Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.
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Affiliation(s)
- Jiaqi LIU
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Chi Tim LEUNG
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China;
| | - Luyun LIANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Yuqin WANG
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - Jian CHEN
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541004, China
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
| | - Keng Po LAI
- Key Laboratory of Environmental Pollution and Integrative Omics, Education Department of Guangxi Zhuang Autonomous Region, Guilin Medical University, Guilin 541004, China; (J.L.); (L.L.); (Y.W.); (K.P.L.)
| | - William Ka Fai TSE
- Laboratory of Developmental Disorders and Toxicology, Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan
- Correspondence: (J.C.); (W.K.F.T.); Tel.: +86-773-5895860 (J.C.); +81-92-802-4767 (W.K.F.T.)
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26
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Kodama T, Kodama M, Jenkins NA, Copeland NG, Chen HJ, Wei Z. Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14112589. [PMID: 35681566 PMCID: PMC9179258 DOI: 10.3390/cancers14112589] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making it difficult to identify driver genes for HCC. To identify HCC driver genes, we performed transposon mutagenesis screens in a mouse HBV model of HCC and discovered many candidate cancer genes (SB/HBV-CCGs). Here, we show that one of these genes, RNF125 is a potent anti-proliferative tumor suppressor gene in HCC. RNF125 is one of nine CCGs whose expression was >3-fold downregulated in human HCC. Depletion of RNF125 in immortalized mouse liver cells led to tumor formation in transplanted mice and accelerated growth of human liver cancer cell lines, while its overexpression inhibited their growth, demonstrating the tumor-suppressive function of RNF125 in mouse and human liver. Whole-transcriptome analysis revealed that RNF125 transcriptionally suppresses multiple genes involved in cell proliferation and/or liver regeneration, including Egfr, Met, and Il6r. Blocking Egfr or Met pathway expression inhibited the increased cell proliferation observed in RNF125 knockdown cells. In HCC patients, low expression levels of RNF125 were correlated with poor prognosis demonstrating an important role for RNF125 in HCC. Collectively, our results identify RNF125 as a novel anti-proliferative tumor suppressor in HCC.
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Affiliation(s)
- Takahiro Kodama
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan
- Correspondence: (T.K.); (Z.W.)
| | - Michiko Kodama
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan
| | - Nancy A. Jenkins
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Neal G. Copeland
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huanhuan Joyce Chen
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA;
- The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Zhubo Wei
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
- Correspondence: (T.K.); (Z.W.)
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27
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Guan T, Yang X, Liang H, Chen J, Chen Y, Zhu Y, Liu T. Deubiquitinating enzyme USP9X regulates metastasis and chemoresistance in triple-negative breast cancer by stabilizing Snail1. J Cell Physiol 2022; 237:2992-3000. [PMID: 35506169 DOI: 10.1002/jcp.30763] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/28/2022] [Accepted: 04/11/2022] [Indexed: 02/06/2023]
Abstract
Breast cancer is one of the most common malignancies in women worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype that has the characteristics of easy recurrence, poor prognosis as well as lack of targeted therapeutics. Snail1, a key factor regulating epithelial-mesenchymal transition (EMT) process, contributing to metastasis and chemoresistance in human cancers. However, the molecular mechanism of Snail1 stabilization in cancers is not fully understood. Here, we demonstrate that the deubiquitinating enzyme USP9X deubiquitinates and stabilizes Snail1, thereby promoting metastasis and chemoresistance. The depletion and pharmacological inhibition of USP9X by WP1130, an inhibitor of USP9X, downregulate endogenous Snail1 protein, inhibit cell migration, invasion, metastasis, and increase cellular sensitivity to cisplatin and paclitaxel both in vitro and in vivo, whereas the reconstitution of Snail1 in cells with USP9X depletion at least partially reverses these phenotypes. Overall, our study establishes the USP9X-Snail1 axis as an important regulatory mechanism of breast cancer metastasis and chemoresistance and provides a rationale for potential therapeutic interventions in the treatment of TNBC.
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Affiliation(s)
- Tangming Guan
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Xiao Yang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Hui Liang
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jiayi Chen
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Yan Chen
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Yingjie Zhu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Tongzheng Liu
- College of Pharmacy, Jinan University, Guangzhou, Guangdong, China
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Zhang FK, Ni QZ, Wang K, Cao HJ, Guan DX, Zhang EB, Ma N, Wang YK, Zheng QW, Xu S, Zhu B, Chen TW, Xia J, Qiu XS, Ding XF, Jiang H, Qiu L, Wang X, Chen W, Cheng SQ, Xie D, Li JJ. Targeting USP9X-AMPK Axis in ARID1A-Deficient Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2022; 14:101-127. [PMID: 35390516 PMCID: PMC9117818 DOI: 10.1016/j.jcmgh.2022.03.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 03/26/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor with high morbidity and mortality. AT-rich interaction domain 1A (ARID1A) accounts for up to 10% of mutations in liver cancer, however, its role in HCC remains controversial, and no targeted therapy has been established. METHODS The expression of ARID1A in clinical samples was examined by Western blot and immunohistochemical staining. ARID1A was knocked out by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) in HCC cell lines, and the effects of glucose deprivation on cell viability, proliferation, and apoptosis were measured. Mass spectrometry analysis was used to find ARID1A-interacting proteins, and the result was verified by co-immunoprecipitation and Glutathione S Transferase (GST) pull-down. The regulation of ARID1A target gene USP9X was investigated by chromatin immunoprecipitation, Glutathione S Transferase (GST) pull-down, luciferase reporter assay, and so forth. Finally, drug treatments were performed to explore the therapeutic potential of the agents targeting ARID1A-deficient HCC in vitro and in vivo. RESULTS Our study has shown that ARID1A loss protected cells from glucose deprivation-induced cell death. A mechanism study disclosed that AIRD1A recruited histone deacetylase 1 via its C-terminal region DUF3518 to the promoter of USP9X, resulting in down-regulation of USP9X and its target protein kinase AMP-activated catalytic subunit α2 (PRKAA2). ARID1A knockout and a 1989∗ truncation mutant in HCC abolished this effect, increased the levels of H3K9 and H3K27 acetylation at the USP9X promoter, and up-regulated the expression of USP9X and protein kinase AMP-activated catalytic subunit α2 (PRKAA2), which mediated the adaptation of tumor cells to glucose starvation. Compound C dramatically inhibited the growth of ARID1A-deficient tumors and prolongs the survival of tumor-bearing mice. CONCLUSIONS HCC patients with ARID1A mutation may benefit from synthetic lethal therapy targeting the ubiquitin-specific peptidase 9 X-linked (USP9X)-adenosine 5'-monophosphate-activated protein kinase (AMPK) axis.
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Affiliation(s)
- Feng-Kun Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qian-Zhi Ni
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Kang Wang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hui-Jun Cao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dong-Xian Guan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Er-Bin Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ning Ma
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yi-Kang Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qian-Wen Zheng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Sheng Xu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Bing Zhu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Tian-Wei Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ji Xia
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiao-Song Qiu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Xu-Fen Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hao Jiang
- Department of Biomedical Informatics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Lin Qiu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiang Wang
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wei Chen
- Cancer Institute of Integrated Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Shu-Qun Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dong Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China; National Health Commission Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, China.
| | - Jing-Jing Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
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Choi HS, Baek KH. Pro-apoptotic and anti-apoptotic regulation mediated by deubiquitinating enzymes. Cell Mol Life Sci 2022; 79:117. [PMID: 35118522 PMCID: PMC11071826 DOI: 10.1007/s00018-022-04132-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/20/2021] [Accepted: 01/05/2022] [Indexed: 12/16/2022]
Abstract
Although damaged cells can be repaired, cells that are considered unlikely to be repaired are eliminated through apoptosis, a type of predicted cell death found in multicellular organisms. Apoptosis is a structured cell death involving alterations to the cell morphology and internal biochemical changes. This process involves the expansion and cracking of cells, changes in cell membranes, nuclear fragmentation, chromatin condensation, and chromosome cleavage, culminating in the damaged cells being eaten and processed by other cells. The ubiquitin-proteasome system (UPS) is a major cellular pathway that regulates the protein levels through proteasomal degradation. This review proposes that apoptotic proteins are regulated through the UPS and describes a unique direction for cancer treatment by controlling proteasomal degradation of apoptotic proteins, and small molecules targeted to enzymes associated with UPS.
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Affiliation(s)
- Hae-Seul Choi
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea.
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Ding P, Ma Z, Fan Y, Feng Y, Shao C, Pan M, Zhang Y, Huang D, Han J, Hu Y, Yan X. Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Rajpurohit T, Bhattacharya S. Moving Towards Dawn: KRas Signaling and Treatment in Pancreatic Ductal Adenocarcinoma. Curr Mol Pharmacol 2022; 15:904-928. [PMID: 35088684 DOI: 10.2174/1874467215666220128161647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
"Pancreatic ductal adenocarcinoma (PDAC)" is robust, nearly clueless, and all-around deadly among all tumors. Below 10 %, the general 5-year endurance period has remained adamantly unaltered in the last 30 years, regardless of enormous clinical and therapeutic endeavors. The yearly number of deaths is more than the number of recently analyzed cases. Not a classic one, but "Carbohydrate Antigen CA19- 9" remains the prevailing tool for diagnosis. MicroRNAs and non-invasive techniques are now incorporated for the effective prognosis of PDAC than just CA19-9. Mutated "Rat sarcoma virus Ras" conformation "V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog KRas" is 95 % accountable for PDAC, and its active (GTP-bound) formation activates signaling cascade comprising "Rapidly accelerated fibrosarcoma Raf"/"Mitogen-activated protein kinase MEK"/ "Extracellular signal-regulated kinase ERK" with "Phosphoinositide 3-kinase PI3K"/ "protein kinase B Akt"/ "mammalian target of rapamycin mTOR" pathways. KRas has acquired the label of 'undruggable' since the crosstalk in the nexus of pathways compensates for Raf and PI3K signaling cascade blocking. It is arduous to totally regulate KRascoordinated PDAC with traditional medicaments like "gemcitabine GEM" plus nabpaclitaxel/ FOLFIRINOX. For long-haul accomplishments aiming at KRas, future endeavors should be directed to combinatorial methodologies to adequately block KRas pathways at different standpoints. Currently they are contributing to healing PDAC. In this review article, we outline the function of KRas in carcinogenesis in PDAC, its signaling cascade, former techniques utilized in hindering Kras, current and future possibilities for targeting Kras.
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Affiliation(s)
- Tarun Rajpurohit
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
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Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma 2021; 8:1415-1444. [PMID: 34858888 PMCID: PMC8630469 DOI: 10.2147/jhc.s336858] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.
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Affiliation(s)
- Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, Istanbul, Turkey
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul, Turkey
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer, Istanbul, 34396, Turkey
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cancer Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Chaouch MA, Leon P, Cassese G, Aguilhon C, Khayat S, Panaro F. Total pancreatectomy with intraportal islet autotransplantation for pancreatic malignancies: a literature overview. Expert Opin Biol Ther 2021; 22:491-497. [PMID: 34747305 DOI: 10.1080/14712598.2022.1990261] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION 'Brittle Diabetes' (BD) is a life-threatening metabolic complication after total pancreatectomy (TP). More than 500 Intraportal islet autotransplantation (IAT) have been performed to prevent this complication, with almost 70% insulin independence after 3 years. Even when insulin independence was not achieved, IAT successfully prevented severe hypoglycemia. Currently, preliminary results for oncologic situations are promising, but their oncological outcomes are still a matter of debate. AREAS COVERED We performed a bibliographic research of the last 25 years of data. Articles published in English in peer-reviewed journals were retained. In France, auto- and allo-islet transplantation was recently recognized as a valuable treatment for BD by the national health authority. While accepted for benign diseases, the risk of tumor spreading after IAT in oncologic situations is a source of concern. EXPERT OPINION Preliminary results of IAT in oncological situations are very encouraging. So far, there is no evidence of tumor dissemination. In our opinion, to overcome BD TP with IAT for resectable pancreatic malignancies in patients with a higher risk of postoperative pancreatic fistula and extended pancreatic cancers can be safely performed. Diagnosis of malignancy should not be considered as an exclusion criterion for IAT.
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Affiliation(s)
- Mohamed Ali Chaouch
- Division of HBP Surgery and Transplantation, Department of Surgery, Montpellier University Hospital, Montpellier, France
| | - Piera Leon
- Division of HBP Surgery and Transplantation, Department of Surgery, Montpellier University Hospital, Montpellier, France
| | - Gianluca Cassese
- Division of HBP Surgery and Transplantation, Department of Surgery, Montpellier University Hospital, Montpellier, France.,Department of Clinical Medicine and Surgery, Federico Ii University, Naples, Italy
| | - Caroline Aguilhon
- Division of Endocrinology, Diabetology and Clinical Nutrition, Montpellier University Hospital, Montpellier, France
| | - Salah Khayat
- Division of HBP Surgery and Transplantation, Department of Surgery, Montpellier University Hospital, Montpellier, France
| | - Fabrizio Panaro
- Division of HBP Surgery and Transplantation, Department of Surgery, Montpellier University Hospital, Montpellier, France
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Tekin C, Scicluna BP, Lodestijn SC, Shi K, Bijlsma MF, Spek CA. Protease-activated receptor 1 drives and maintains ductal cell fates in the premalignant pancreas and ductal adenocarcinoma. Mol Oncol 2021; 15:3091-3108. [PMID: 33932087 PMCID: PMC8564660 DOI: 10.1002/1878-0261.12971] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 02/26/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic acinar cells have high plasticity and can transdifferentiate into ductal-like cells. This acinar-to-ductal metaplasia (ADM) contributes to tissue maintenance but may also contribute to the premalignant transformation that can eventually progress to pancreatic ductal adenocarcinoma (PDAC). Macrophages are key players in ADM, and macrophage-secreted matrix metalloproteinase (MMP)-9 induces ADM through yet unknown mechanisms. As we previously identified MMP9 as a novel agonist of protease-activated receptor 1 (PAR1), a receptor that is known to orchestrate the cross-talk between macrophages and tumor cells in PDAC, we here assessed the contribution of PAR1 to pancreatic cell fates. We found that genetic deficiency for PAR1 increases acinar gene expression programs in the healthy pancreas and that PAR1 deficiency limits ductal transdifferentiation in experimental systems for ADM. Moreover, PAR1 silencing in PDAC cells increases acinar marker expression. Changes in PDAC cell lines were associated with a downregulation of known Myc-target genes, and Myc inhibition mimics PAR1 deficiency in enhancing acinar programs in healthy organoids and PDAC cells. Overall, we identify the PAR1-Myc axis as a driver of ductal cell fates in premalignant pancreas and PDAC. Moreover, we show that cellular plasticity is not unique to acinar cells and that ductal regeneration into acinar-like cells is possible even in the context of oncogenic KRAS activation.
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Affiliation(s)
- Cansu Tekin
- Center for Experimental and Molecular MedicineAmsterdam UMCUniversity of AmsterdamThe Netherlands
- Laboratory for Experimental Oncology and RadiobiologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Brendon P. Scicluna
- Center for Experimental and Molecular MedicineAmsterdam UMCUniversity of AmsterdamThe Netherlands
| | - Sophie C. Lodestijn
- Laboratory for Experimental Oncology and RadiobiologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - Kun Shi
- Center for Experimental and Molecular MedicineAmsterdam UMCUniversity of AmsterdamThe Netherlands
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and RadiobiologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamThe Netherlands
- Oncode InstituteAmsterdamThe Netherlands
| | - C. Arnold Spek
- Center for Experimental and Molecular MedicineAmsterdam UMCUniversity of AmsterdamThe Netherlands
- Laboratory for Experimental Oncology and RadiobiologyCancer Center AmsterdamAmsterdam UMCUniversity of AmsterdamThe Netherlands
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Miquel M, Zhang S, Pilarsky C. Pre-clinical Models of Metastasis in Pancreatic Cancer. Front Cell Dev Biol 2021; 9:748631. [PMID: 34778259 PMCID: PMC8578999 DOI: 10.3389/fcell.2021.748631] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a hostile solid malignancy coupled with an extremely high mortality rate. Metastatic disease is already found in most patients at the time of diagnosis, resulting in a 5-year survival rate below 5%. Improved comprehension of the mechanisms leading to metastasis is pivotal for the development of new targeted therapies. A key field to be improved are modeling strategies applied in assessing cancer progression, since traditional platforms fail in recapitulating the complexity of PDAC. Consequently, there is a compelling demand for new preclinical models that mirror tumor progression incorporating the pressure of the immune system, tumor microenvironment, as well as molecular aspects of PDAC. We suggest the incorporation of 3D organoids derived from genetically engineered mouse models or patients as promising new tools capable to transform PDAC pre-clinical modeling and access new frontiers in personalized medicine.
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Affiliation(s)
- Maria Miquel
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Shuman Zhang
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Christian Pilarsky
- Department of Surgery, University Hospital, Erlangen, Germany
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer. Proc Natl Acad Sci U S A 2021; 118:2101592118. [PMID: 34518219 DOI: 10.1073/pnas.2101592118] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2021] [Indexed: 01/12/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.
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Sulkshane P, Pawar SN, Waghole R, Pawar SS, Rajput P, Uthale A, Oak S, Kalkar P, Wani H, Patil R, Nair S, Rane P, Teni T. Elevated USP9X drives early-to-late-stage oral tumorigenesis via stabilisation of anti-apoptotic MCL-1 protein and impacts outcome in oral cancers. Br J Cancer 2021; 125:547-560. [PMID: 34079080 PMCID: PMC8367974 DOI: 10.1038/s41416-021-01421-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 03/17/2021] [Accepted: 04/22/2021] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. METHODS Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. RESULTS Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. CONCLUSION We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.
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Affiliation(s)
- Prasad Sulkshane
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra India ,grid.6451.60000000121102151Present Address: Glickman Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
| | - Sagar N. Pawar
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India
| | - Rohit Waghole
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India
| | - Sushil S. Pawar
- KBH Dental College and Hospital, Panchwati, Nashik, Maharashtra India
| | - Priyanka Rajput
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India
| | - Abhay Uthale
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra India
| | - Swapnil Oak
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra India
| | - Prajakta Kalkar
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India
| | - Harshada Wani
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India
| | - Rahul Patil
- KBH Dental College and Hospital, Panchwati, Nashik, Maharashtra India
| | - Sudhir Nair
- grid.450257.10000 0004 1775 9822Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra India ,grid.410871.b0000 0004 1769 5793Department of Surgical Oncology, Tata Memorial Centre, Mumbai, Maharashtra India
| | - Pallavi Rane
- grid.410869.20000 0004 1766 7522Clinical Research Secretariat, ACTREC, TMC, Kharghar, Navi Mumbai, Maharashtra India
| | - Tanuja Teni
- grid.410871.b0000 0004 1769 5793Teni Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, Maharashtra India ,grid.450257.10000 0004 1775 9822Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra India
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Aiderus A, Newberg JY, Guzman-Rojas L, Contreras-Sandoval AM, Meshey AL, Jones DJ, Amaya-Manzanares F, Rangel R, Ward JM, Lee SC, Ban KHK, Rogers K, Rogers SM, Selvanesan L, McNoe LA, Copeland NG, Jenkins NA, Tsai KY, Black MA, Mann KM, Mann MB. Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression. PLoS Genet 2021; 17:e1009094. [PMID: 34398873 PMCID: PMC8389471 DOI: 10.1371/journal.pgen.1009094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 08/26/2021] [Accepted: 07/14/2021] [Indexed: 12/01/2022] Open
Abstract
The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates. Non-melanoma skin cancers, the most common cancers in the US, are caused by UV skin exposure. Nearly 1 million cases of cutaneous squamous cell carcinoma (cuSCC) are diagnosed in the US each year. While most cuSCCs are highly treatable, more than twice as many individuals die from this disease as from melanoma. The high burden of UV-induced DNA damage in human skin poses a challenge for identifying initiating and cooperating mutations that promote cuSCC development and for defining potential therapeutic targets. Here, we describe a genetic screen in mice using a DNA transposon system to mutagenize the genome of keratinocytes and drive squamous cell carcinoma in the absence of UV. By sequencing where the transposons selectively integrated in the genomes of normal skin, skin with pre-cancerous lesions and skin with fully developed cuSCCs from our mouse model, we were able to identify frequently mutated genes likely important for this disease. Our analysis also defined cooperation between sets of genes not previously appreciated in cuSCC. Our mouse model and ensuing data provide a framework for understanding the genetics of cuSCC and for defining the molecular changes that may lead to the future therapies for patients.
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Affiliation(s)
- Aziz Aiderus
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Justin Y. Newberg
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Liliana Guzman-Rojas
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Ana M. Contreras-Sandoval
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Amanda L. Meshey
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Devin J. Jones
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Felipe Amaya-Manzanares
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Roberto Rangel
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
| | - Jerrold M. Ward
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Song-Choon Lee
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Kenneth Hon-Kim Ban
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Keith Rogers
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Susan M. Rogers
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Luxmanan Selvanesan
- Centre for Translational Cancer Research, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Leslie A. McNoe
- Centre for Translational Cancer Research, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Neal G. Copeland
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Nancy A. Jenkins
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
| | - Kenneth Y. Tsai
- Departments of Anatomic Pathology & Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Michael A. Black
- Centre for Translational Cancer Research, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Karen M. Mann
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- Departments of Gastrointestinal Oncology & Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Cancer Biology and Evolution Program, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
| | - Michael B. Mann
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas, United States of America
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Republic of Singapore
- Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- Cancer Biology and Evolution Program, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, Florida, United States of America
- * E-mail:
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Epigenetic Alterations in Pancreatic Cancer Metastasis. Biomolecules 2021; 11:biom11081082. [PMID: 34439749 PMCID: PMC8394313 DOI: 10.3390/biom11081082] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/16/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.
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Slapak EJ, Kong L, el Mandili M, Nieuwland R, Kros A, Bijlsma MF, Spek CA. ADAM9-Responsive Mesoporous Silica Nanoparticles for Targeted Drug Delivery in Pancreatic Cancer. Cancers (Basel) 2021; 13:3321. [PMID: 34282781 PMCID: PMC8268056 DOI: 10.3390/cancers13133321] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate of all cancers. This poor prognosis results from the lack of efficient systemic treatment regimens, demanding high-dose chemotherapy that causes severe side effects. To overcome dose-dependent toxicities, we explored the efficacy of targeted drug delivery using a protease-dependent drug-release system. To this end, we developed a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSN) functionalized with an avidin-biotin gatekeeper system containing a protease linker that is specifically cleaved by tumor cells. Bioinformatic analysis identified ADAM9 as a PDAC-enriched protease, and PDAC cell-derived conditioned medium efficiently cleaved protease linkers containing ADAM9 substrates. Cleavage was PDAC specific as conditioned medium from leukocytes was unable to cleave the ADAM9 substrate. Protease linker-functionalized MSNs were efficiently capped with avidin, and cap removal was confirmed to occur in the presence of PDAC cell-derived ADAM9. Subsequent treatment of PDAC cells in vitro with paclitaxel-loaded MSNs indeed showed high cytotoxicity, whereas no cell death was observed in white blood cell-derived cell lines, confirming efficacy of the nanoparticle-mediated drug delivery system. Taken together, this research introduces a novel ADAM9-responsive, protease-dependent, drug delivery system for PDAC as a promising tool to reduce the cytotoxicity of systemic chemotherapy.
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Affiliation(s)
- Etienne J. Slapak
- Center of Experimental and Molecular Medicine, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
- Laboratory for Experimental Oncology and Radiobiology, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - Lily Kong
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China; (L.K.); (A.K.)
| | - Mouad el Mandili
- Center of Experimental and Molecular Medicine, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
- Laboratory for Experimental Oncology and Radiobiology, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
| | - Rienk Nieuwland
- Laboratory of Experimental Clinical Chemistry, Department of Clinical Chemistry, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands;
- Vesicle Observation Center, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands
| | - Alexander Kros
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China; (L.K.); (A.K.)
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - C. Arnold Spek
- Center of Experimental and Molecular Medicine, University of Amsterdam and Cancer Center Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; (M.e.M.); (C.A.S.)
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Takeda H, Jenkins NA, Copeland NG. Identification of cancer driver genes using Sleeping Beauty transposon mutagenesis. Cancer Sci 2021; 112:2089-2096. [PMID: 33783919 PMCID: PMC8177796 DOI: 10.1111/cas.14901] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer genome sequencing studies have identified driver genes for a variety of different cancers and helped to understand the genetic landscape of human cancer. It is still challenging, however, to identify cancer driver genes with confidence simply from genetic data alone. In vivo forward genetic screens using Sleeping Beauty (SB) transposon mutagenesis provides another powerful genetic tool for identifying candidate cancer driver genes in wild-type and sensitized mouse tumors. By comparing cancer driver genes identified in human and mouse tumors, cancer driver genes can be identified with additional confidence based upon comparative oncogenomics. This review describes how SB mutagenesis works in mice and focuses on studies that have identified cancer driver genes in the mouse gastrointestinal tract.
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Affiliation(s)
- Haruna Takeda
- Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Nancy A Jenkins
- Laboratory of Molecular Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Neal G Copeland
- Genetics Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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The Association between TIF1 Family Members and Cancer Stemness in Solid Tumors. Cancers (Basel) 2021; 13:cancers13071528. [PMID: 33810347 PMCID: PMC8061774 DOI: 10.3390/cancers13071528] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Stem cell-associated molecular features of solid tumors, collectively known as cancer stemness, are of great importance in the development, progression, and reoccurrence of cancer. Transcriptional and epigenetic dysregulation is significantly associated with cancer stemness. Here, we investigated the association between the Transcriptional Intermediary Factor 1 (TIF1) family members and cancer stemness in solid tumors. We aimed to evaluate the potential value of TIF1 members in predicting a stem-like cancer phenotype. Our results indicate that only TIF1β (also known as Tripartite Motif protein 28, TRIM28) high expression is consequently associated with a “stemness high” phenotype, regardless of the tumor type, resulting in a worse prognosis for cancer patients. The oncogenic signature of TRIM28HIGH tumors significantly reflects the enrichment of “stemness high” cancers with targets for c-Myc (MYC Proto-Oncogene). TRIM28-associated gene expression profiles are also robustly enriched with stemness markers. Our results demonstrate that the association between high TRIM28 expression and an enriched cancer stem cell-like phenotype is a common phenomenon across solid tumors. Abstract Cancer progression entails a gradual loss of a differentiated phenotype in parallel with the acquisition of stem cell-like features. Cancer de-differentiation and the acquisition of stemness features are mediated by the transcriptional and epigenetic dysregulation of cancer cells. Here, using publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and harnessing several bioinformatic tools, we characterized the association between Transcriptional Intermediary Factor 1 (TIF1) family members and cancer stemness in 27 distinct types of solid tumors. We aimed to define the prognostic value for TIF1 members in predicting a stem cell-like cancer phenotype and patient outcome. Our results demonstrate that high expression of only one member of the TIF1 family, namely TIF1β (also known as Tripartite Motif protein 28, TRIM28) is consequently associated with enriched cancer stemness across the tested solid tumor types, resulting in a worse prognosis for cancer patients. TRIM28 is highly expressed in higher grade tumors that exhibit stem cell-like traits. In contrast to other TIF1 members, only TIF1β/TRIM28-associated gene expression profiles were robustly enriched with stemness markers regardless of the tumor type. Our work demonstrates that TIF1 family members exhibit distinct expression patterns in stem cell-like tumors, despite their structural and functional similarity. Among other TIF1 members, only TRIM28 might serve as a marker of cancer stemness features.
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Chen E, Li E, Liu H, Zhou Y, Wen L, Wang J, Wang Y, Ye L, Liang T. miR-26b enhances the sensitivity of hepatocellular carcinoma to Doxorubicin via USP9X-dependent degradation of p53 and regulation of autophagy. Int J Biol Sci 2021; 17:781-795. [PMID: 33767588 PMCID: PMC7975695 DOI: 10.7150/ijbs.52517] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/16/2021] [Indexed: 12/30/2022] Open
Abstract
Multi-drug resistance is a major challenge to hepatocellular carcinoma (HCC) treatment, and the over-expression or deletion of microRNA (miRNA) expression is closely related to the drug-resistant properties of various cell lines. However, the underlying molecular mechanisms remain unclear. CCK-8, EdU, flow cytometry, and transmission electron microscopy were performed to determine cell viability, proliferation, apoptosis, autophagic flow, and nanoparticle characterization, respectively. In this study, the results showed that the expression of miR-26b was downregulated following doxorubicin treatment in human HCC tissues. An miR-26b mimic enhanced HCC cell doxorubicin sensitivity, except in the absence of p53 in Hep3B cells. Delivery of the proteasome inhibitor, MG132, reversed the inhibitory effect of miR-26b on the level of p53 following doxorubicin treatment. Tenovin-1 (an MDM2 inhibitor) protected p53 from ubiquitination-mediated degradation only in HepG2 cells with wild type p53. Tenovin-1 pretreatment enhanced HCC cell resistance to doxorubicin when transfected with an miR-26b mimic. Moreover, the miR-26b mimic inhibited doxorubicin-induced autophagy and the autophagy inducer, rapamycin, eliminated the differences in the drug sensitivity effect of miR-26b. In vivo, treatment with sp94dr/miR-26b mimic nanoparticles plus doxorubicin inhibited tumor growth. Our current data indicate that miR-26b enhances HCC cell sensitivity to doxorubicin through diminishing USP9X-mediated p53 de-ubiquitination caused by DNA damaging drugs and autophagy regulation. This miRNA-mediated pathway that modulates HCC will help develop novel therapeutic strategies.
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Affiliation(s)
- Enjiang Chen
- The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Enliang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Liu
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yi Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Medical Oncology, Tongde hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Tingbo Liang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Innovation Center for the Study of Pancreatic Disease, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
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Aiderus A, Contreras-Sandoval AM, Meshey AL, Newberg JY, Ward JM, Swing DA, Copeland NG, Jenkins NA, Mann KM, Mann MB. Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation. Cancers (Basel) 2021; 13:E225. [PMID: 33435458 PMCID: PMC7827284 DOI: 10.3390/cancers13020225] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 12/19/2022] Open
Abstract
A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.
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Affiliation(s)
- Aziz Aiderus
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
| | - Ana M. Contreras-Sandoval
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
| | - Amanda L. Meshey
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
| | - Justin Y. Newberg
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
- Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (N.G.C.); (N.A.J.)
| | - Jerrold M. Ward
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore;
| | - Deborah A. Swing
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
| | - Neal G. Copeland
- Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (N.G.C.); (N.A.J.)
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore;
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
| | - Nancy A. Jenkins
- Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (N.G.C.); (N.A.J.)
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore;
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
| | - Karen M. Mann
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
- Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (N.G.C.); (N.A.J.)
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore;
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
- Departments of Gastrointestinal Oncology & Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Cancer Biology and Evolution Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Michael B. Mann
- Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; (A.A.); (A.M.C.-S.); (A.L.M.); (J.Y.N.)
- Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA; (N.G.C.); (N.A.J.)
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore;
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA;
- Cancer Biology and Evolution Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, Tampa, FL 33612, USA
- Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
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Hu X, Wang J, Chu M, Liu Y, Wang ZW, Zhu X. Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy. Mol Ther 2021; 29:908-919. [PMID: 33388422 DOI: 10.1016/j.ymthe.2020.12.032] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/09/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
A growing amount of evidence suggests that ubiquitination and deubiquitination of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) play crucial roles in the regulation of PD-1 and PD-L1 protein stabilization and dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway that modulates immune escape in cancer patients, and its engagement and inhibition has significantly reshaped the landscape of tumor clearance. The abnormal ubiquitination and deubiquitination of PD-1/PD-L1 influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe the ubiquitination- and deubiquitination-mediated modulation of PD-1/PD-L1 signaling through a variety of E3 ligases and deubiquitinating enzymes (DUBs). Moreover, we briefly expound on the anticancer potential of some agents that target related E3 ligases, which further modulate the ubiquitination of PD-1/PD-L1 in cancers. Therefore, this review reveals the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination.
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Affiliation(s)
- Xiaoli Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Jing Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Man Chu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Yi Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Zhi-Wei Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
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Jolly LA, Parnell E, Gardner AE, Corbett MA, Pérez-Jurado LA, Shaw M, Lesca G, Keegan C, Schneider MC, Griffin E, Maier F, Kiss C, Guerin A, Crosby K, Rosenbaum K, Tanpaiboon P, Whalen S, Keren B, McCarrier J, Basel D, Sadedin S, White SM, Delatycki MB, Kleefstra T, Küry S, Brusco A, Sukarova-Angelovska E, Trajkova S, Yoon S, Wood SA, Piper M, Penzes P, Gecz J. Missense variant contribution to USP9X-female syndrome. NPJ Genom Med 2020; 5:53. [PMID: 33298948 PMCID: PMC7725775 DOI: 10.1038/s41525-020-00162-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/29/2020] [Indexed: 02/06/2023] Open
Abstract
USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.
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Affiliation(s)
- Lachlan A Jolly
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia.
| | - Euan Parnell
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Alison E Gardner
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia
| | - Mark A Corbett
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia
| | - Luis A Pérez-Jurado
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia
- Women's and Children's Hospital, Adelaide, SA, 5006, Australia
- South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
- Hospital del Mar Research Institute (IMIM), Network Research Centre for Rare Diseases (CIBERER) and Universitat Pompeu Fabra, Barcelona, 08003, Spain
| | - Marie Shaw
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia
| | - Gaetan Lesca
- Institut Neuromyogène, métabolisme énergétique et développement durable, CNRS UMR 5310, INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
- Service de Génétique, Hospices Civils de Lyon, Lyon, France
| | - Catherine Keegan
- Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Michael C Schneider
- Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Emily Griffin
- Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Felicitas Maier
- Dr. von Hauner Children's Hospital, LMU - Ludwig-Maximilians-Universität Munich, University of Munich Medical Center, Munich, Germany
| | - Courtney Kiss
- Kingston Health Sciences Centre, Kingston, ON, K7L 2V7, Canada
| | - Andrea Guerin
- Division of Medical Genetics, Department of Pediatrics, Kingston General Hospital, Kingston, ON, Canada
| | - Kathleen Crosby
- Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA
| | - Kenneth Rosenbaum
- Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA
| | - Pranoot Tanpaiboon
- Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA
| | - Sandra Whalen
- Unité Fonctionnelle de génétique clinique, Hôpital Armand Trousseau, Assistance publique-Hôpitaux de Paris, Centre de Référence Maladies Rares des anomalies du développement et syndromes malformatifs, Paris, France
| | - Boris Keren
- Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France
| | - Julie McCarrier
- Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Donald Basel
- Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Simon Sadedin
- Victorian Clinical Genetics Service, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Susan M White
- Victorian Clinical Genetics Service, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Martin B Delatycki
- Victorian Clinical Genetics Service, Melbourne, VIC, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Tjitske Kleefstra
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6500, HB, the Netherlands
| | - Sébastien Küry
- Service de Génétique Médicale, CHU Nantes, 44093, Nantes, France
- l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, 44007, Nantes, France
| | - Alfredo Brusco
- Department of Medical Sciences, University of Turin, Torino, Italy
- Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, Italy
| | - Elena Sukarova-Angelovska
- Department of Endocronology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia
| | - Slavica Trajkova
- Department of Medical Sciences, University of Turin, Torino, Italy
| | - Sehoun Yoon
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Stephen A Wood
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia
| | - Michael Piper
- School of Biomedical Sciences, University of Queensland, Brisbane, QLD, 4072, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Peter Penzes
- Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Il, USA
| | - Jozef Gecz
- University of Adelaide and Robinson Research Institute, Adelaide, SA, 5005, Australia.
- South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia.
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Bonacci T, Emanuele MJ. Dissenting degradation: Deubiquitinases in cell cycle and cancer. Semin Cancer Biol 2020; 67:145-158. [PMID: 32201366 PMCID: PMC7502435 DOI: 10.1016/j.semcancer.2020.03.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/27/2020] [Accepted: 03/09/2020] [Indexed: 01/01/2023]
Abstract
Since its discovery forty years ago, protein ubiquitination has been an ever-expanding field. Virtually all biological processes are controlled by the post-translational conjugation of ubiquitin onto target proteins. In addition, since ubiquitin controls substrate degradation through the action of hundreds of enzymes, many of which represent attractive therapeutic candidates, harnessing the ubiquitin system to reshape proteomes holds great promise for improving disease outcomes. Among the numerous physiological functions controlled by ubiquitin, the cell cycle is among the most critical. Indeed, the discovery that the key drivers of cell cycle progression are regulated by the ubiquitin-proteasome system (UPS) epitomizes the connection between ubiquitin signaling and proliferation. Since cancer is a disease of uncontrolled cell cycle progression and proliferation, targeting the UPS to stop cancer cells from cycling and proliferating holds enormous therapeutic potential. Ubiquitination is reversible, and ubiquitin is removed from substrates by catalytic proteases termed deubiquitinases or DUBs. While ubiquitination is tightly linked to proliferation and cancer, the role of DUBs represents a layer of complexity in this landscape that remains poorly captured. Due to their ability to remodel the proteome by altering protein degradation dynamics, DUBs play an important and underappreciated role in the cell cycle and proliferation of both normal and cancer cells. Moreover, due to their enzymatic protease activity and an open ubiquitin binding pocket, DUBs are likely to be important in the future of cancer treatment, since they are among the most druggable enzymes in the UPS. In this review we summarize new and important findings linking DUBs to cell cycle and proliferation, as well as to the etiology and treatment of cancer. We also highlight new advances in developing pharmacological approaches to attack DUBs for therapeutic benefit.
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Affiliation(s)
- Thomas Bonacci
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States
| | - Michael J Emanuele
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States.
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Liu D, Steins A, Klaassen R, van der Zalm AP, Bennink RJ, van Tienhoven G, Besselink MG, Bijlsma MF, van Laarhoven HWM. Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma. Biomedicines 2020; 8:biomedicines8110444. [PMID: 33105540 PMCID: PMC7690284 DOI: 10.3390/biomedicines8110444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and a hypoxic microenvironment. Pancreatic stellate cells (PSC) are activated by hypoxia and promote excessive desmoplasia, further contributing to the development of hypoxia. We aimed to explore how hypoxia and stroma interact to contribute to invasive growth in PDAC. [18F]HX4 PET/CT was found to be a feasible non-invasive method to assess tumor hypoxia in 42 patients and correlated with HIF1α immunohistochemistry in matched surgical specimens. [18F]HX4 uptake and HIF1α were strong prognostic markers for overall survival. Co-culture and medium transfer experiments demonstrated that hypoxic PSCs and their supernatant induce upregulation of mesenchymal markers in tumor cells, and that hypoxia-induced stromal factors drive invasive growth in hypoxic PDACs. Through stepwise selection, stromal MMP10 was identified as the most likely candidate responsible for this. In conclusion, hypoxia-activated PSCs promote the invasiveness of PDAC through paracrine signaling. The identification of PSC-derived MMP10 may provide a lead to develop novel stroma-targeting therapies.
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Affiliation(s)
- Dajia Liu
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Anne Steins
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Remy Klaassen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Amber P. van der Zalm
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
| | - Roel J. Bennink
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Geertjan van Tienhoven
- Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Marc G. Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands; (D.L.); (A.S.); (R.K.); (A.P.v.d.Z.)
- Oncode Institute, 1105 AZ Amsterdam, The Netherlands
- Correspondence: ; Tel.: +31-(0)20-5664824
| | - Hanneke W. M. van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands;
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Weber J, Braun CJ, Saur D, Rad R. In vivo functional screening for systems-level integrative cancer genomics. Nat Rev Cancer 2020; 20:573-593. [PMID: 32636489 DOI: 10.1038/s41568-020-0275-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2020] [Indexed: 02/06/2023]
Abstract
With the genetic portraits of all major human malignancies now available, we next face the challenge of characterizing the function of mutated genes, their downstream targets, interactions and molecular networks. Moreover, poorly understood at the functional level are also non-mutated but dysregulated genomes, epigenomes or transcriptomes. Breakthroughs in manipulative mouse genetics offer new opportunities to probe the interplay of molecules, cells and systemic signals underlying disease pathogenesis in higher organisms. Herein, we review functional screening strategies in mice using genetic perturbation and chemical mutagenesis. We outline the spectrum of genetic tools that exist, such as transposons, CRISPR and RNAi and describe discoveries emerging from their use. Genome-wide or targeted screens are being used to uncover genomic and regulatory landscapes in oncogenesis, metastasis or drug resistance. Versatile screening systems support experimentation in diverse genetic and spatio-temporal settings to integrate molecular, cellular or environmental context-dependencies. We also review the combination of in vivo screening and barcoding strategies to study genetic interactions and quantitative cancer dynamics during tumour evolution. These scalable functional genomics approaches are transforming our ability to interrogate complex biological systems.
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Affiliation(s)
- Julia Weber
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany
| | - Christian J Braun
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, Germany
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dieter Saur
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany
- Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Roland Rad
- Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, Munich, Germany.
- Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, Munich, Germany.
- Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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50
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Linkage of genetic drivers and strain-specific germline variants confound mouse cancer genome analyses. Nat Commun 2020; 11:4474. [PMID: 32901003 PMCID: PMC7479137 DOI: 10.1038/s41467-020-18095-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/27/2020] [Indexed: 01/14/2023] Open
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