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Ozsagir E, Ercin ME, Celep Eyuboglu F, Osmanagaoglu MA. P53 Puzzle: WWP1 and PARC Immunohistochemistry Illuminate New Pathways for Serous Ovarian Cancer. Appl Immunohistochem Mol Morphol 2025:00129039-990000000-00221. [PMID: 40248870 DOI: 10.1097/pai.0000000000001260] [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: 11/20/2024] [Accepted: 03/18/2025] [Indexed: 04/19/2025]
Abstract
High-grade serous carcinoma is categorized based on p53 mutation status. A relationship is known to exist between p53 mutations and p53 immunoexpression patterns, including overexpression, complete absence, cytoplasmic, and wild-type patterns. The ubiquitin ligases WWP1 and PARC, known to regulate p53 activation, are hypothesized to influence the pathogenesis of serous ovarian tumors. This retrospective study examined 7 low-grade serous carcinomas, 38 high-grade serous carcinomas, and 15 serous cystadenomas, with immunohistochemical analyses performed for WWP1, PARC, and p53. High-grade serous carcinoma cases were classified into wild-type, cytoplasmic, complete absence, or overexpression categories based on p53 immunohistochemistry. PARC and WWP1 expressions were compared across p53 categories and diagnoses. Results showed a statistically significant reduction in WWP1 and PARC expression in serous carcinomas, with the most pronounced loss observed in high-grade cases. Among morphologically classified high-grade carcinomas, 17 overexpression, 11 complete absence, 6 wild-type, and 4 cytoplasmic p53 cases were identified. A statistically significant relationship was found between PARC, WWP1, and p53 status. Higher expression levels of PARC and WWP1 were detected in p53 wild-type cases, whereas lower expression levels were associated with cases exhibiting p53 overexpression and complete absence. This study suggests that PARC and WWP1 play a role in the pathogenesis of high-grade serous ovarian carcinoma, potentially mediated by p53, making them promising targets for treatment and prognostic markers in serous ovarian cancer.
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Affiliation(s)
- Elif Ozsagir
- Department of Pathology, Bingol State Hospital, Bingol
| | - Mustafa E Ercin
- Department of Pathology, Lokman Hekim University Faculty of Medicine, Ankara
| | | | - Mehmet A Osmanagaoglu
- Department of Obstetrics and Gynecology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey
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Notoya G, Kishikawa T, Yasugi K, Iwata T, Seimiya T, Miyabayashi K, Takahashi R, Yamamoto K, Ijichi H, Otsuka M, Fujishiro M. WWP1 inhibition suppresses the proliferation of pancreatic cancer cells by regulating the PI3K-AKT pathway. J Gastroenterol 2025; 60:370-384. [PMID: 39656237 PMCID: PMC11880106 DOI: 10.1007/s00535-024-02192-x] [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: 09/12/2024] [Accepted: 11/23/2024] [Indexed: 02/07/2025]
Abstract
BACKGROUND The proto-oncogene WWP1 is overexpressed in various cancers and contributes to tumor growth and poor prognosis. Recently, WWP1 inhibition was reported to suppress tumor development and cell proliferation by activating the PTEN function. However, the expression profiles and clinical significance of WWP1 in pancreatic ductal adenocarcinoma (PDAC) tissues remain undetermined. Therefore, this study aimed to evaluate the WWP1 expression in PDAC and investigate the therapeutic potential of WWP1 inhibition. METHODS Cellular proliferation assays were performed using a doxycycline-inducible shWWP1 expression system. Transcriptome analyses were conducted to identify the altered pathways in WWP1-depleted cells. PTEN ubiquitination by WWP1 was confirmed using immunoprecipitation assays. In vivo xenograft and drug screening assays were performed to evaluate the clinical significance of WWP1 inhibition. RESULTS WWP1 was significantly upregulated in PDAC tissues and associated with poor prognosis. WWP1 depletion significantly reduced the proliferation of PDAC cell lines, correlating with the suppression of the PI3K-AKT pathway. Mechanistically, as reported in other cancer types, PTEN is a target of WWP1 in PDAC cells. PTEN silencing abrogated the growth-inhibitory effects in WWP1-depleted cells, suggesting that the anti-tumor effects of WWP1 inhibition are mediated through PTEN activation. In vivo xenograft studies confirmed that WWP1 depletion substantially inhibited tumor growth. Moreover, drug screening assays revealed that WWP1 depletion had an additive effect with the PI3K-AKT pathway inhibitors on hindering tumor growth. CONCLUSION WWP1 inhibition enhances the anti-tumor effects of PI3K-AKT pathway inhibitors through PTEN activation. Thus, WWP1 could be a potential therapeutic target in PDAC.
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Grants
- 22K15390 Ministry of Education, Culture, Sports, Science and Technology
- 22K19517 Ministry of Education, Culture, Sports, Science and Technology
- 21H02893 Ministry of Education, Culture, Sports, Science and Technology
- 22H02828 Ministry of Education, Culture, Sports, Science and Technology
- JP23ck0106807 Japan Agency for Medical Research and Development
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Kobayashi Foundation for Cancer Research
- The University of Tokyo
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Affiliation(s)
- Genso Notoya
- Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Kengo Yasugi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takuma Iwata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Ryota Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Keisuke Yamamoto
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Hideaki Ijichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Clinical Nutrition Center, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Ganesan IP, Kiyokawa H. A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins. Cancers (Basel) 2025; 17:626. [PMID: 40002221 PMCID: PMC11853300 DOI: 10.3390/cancers17040626] [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: 12/31/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated degradation in cancers emerge as promising therapeutic targets. Unlike proteasomal inhibitors with a broad spectrum, inhibitors of an E3 ligase would offer superior selectivity and efficacy in enhancing expression of its substrate TS proteins as far as the TS proteins retain wild-type structures. Recent advances in developing E3 inhibitors, including MDM2 inhibitors, highlight their potential and ultimately guide the framework to establish E3 inhibition as effective strategies to treat specific types of cancers. This review explores E3 ligases that negatively regulate bona fide TS proteins, the developmental status of E3 inhibitors, and their promise and pitfalls as therapeutic agents for anti-cancer precision medicine.
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Affiliation(s)
| | - Hiroaki Kiyokawa
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
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Giovannini S, Li Y, Pecorari R, Fierro C, Fiorilli C, Corigliano F, Moriconi V, Zhou J, De Antoni A, Smirnov A, Rinalducci S, Timperio AM, Agostini M, Zhang J, Shi Y, Candi E, Melino G, Bernassola F. Thioredoxin-interacting protein (TXNIP) is a substrate of the NEDD4-like E3 ubiquitin-protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells. Mol Oncol 2025; 19:133-150. [PMID: 39364720 PMCID: PMC11705725 DOI: 10.1002/1878-0261.13722] [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: 01/22/2024] [Revised: 06/29/2024] [Accepted: 08/05/2024] [Indexed: 10/05/2024] Open
Abstract
The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin-dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1-depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up-take and consumption. Hence, a contribution to the increased cell death observed in WWP1-depleted cells also possibly arises from the attenuation of glucose up-take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP-dependent deregulation of redox homeostasis in WWP1-overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.
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Affiliation(s)
- Sara Giovannini
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
| | - Yanan Li
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow UniversitySuzhouChina
| | - Rosalba Pecorari
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
- Biochemistry LaboratoryIstituto Dermopatico Immacolata (IDI‐IRCCS)RomeItaly
| | - Claudia Fierro
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
| | - Claudia Fiorilli
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
| | | | - Valeria Moriconi
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
| | - Ji Zhou
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
- Institutes of Biology and Medical Sciences, Suzhou Medical CollegeSoochow UniversitySuzhouChina
| | - Anna De Antoni
- IFOM ETS‐The AIRC Institute of Molecular OncologyMilanItaly
| | - Artem Smirnov
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
- Biochemistry LaboratoryIstituto Dermopatico Immacolata (IDI‐IRCCS)RomeItaly
| | - Sara Rinalducci
- Department of Ecological and Biological SciencesUniversity of TusciaViterboItaly
| | - Anna Maria Timperio
- Department of Ecological and Biological SciencesUniversity of TusciaViterboItaly
| | | | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Suzhou Medical CollegeSoochow UniversitySuzhouChina
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow UniversitySuzhouChina
| | - Eleonora Candi
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
- Biochemistry LaboratoryIstituto Dermopatico Immacolata (IDI‐IRCCS)RomeItaly
| | - Gerry Melino
- Department of Experimental Medicine, TORUniversity of Rome Tor VergataItaly
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Perron T, Boissan M, Bièche I, Courtois L, Dingli F, Loew D, Chouchène M, Colasse S, Levy L, Prunier C. CYYR1 promotes the degradation of the E3 ubiquitin ligase WWP1 and is associated with favorable prognosis in breast cancer. J Biol Chem 2024; 300:107601. [PMID: 39059493 PMCID: PMC11399591 DOI: 10.1016/j.jbc.2024.107601] [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: 03/29/2024] [Revised: 06/26/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Ubiquitination plays a crucial role in cellular homeostasis by regulating the degradation, localization, and activity of proteins, ensuring proper cell function and balance. Among E3 ubiquitin ligases, WW domain-containing protein 1 (WWP1) is implicated in cell proliferation, survival, and apoptosis. Notably WWP1 is frequently amplified in breast cancer and associated with poor prognosis. Here, we identify the protein cysteine and tyrosine-rich protein 1 (CYYR1) that had previously no assigned function, as a regulator of WWP1 activity and stability. We show that CYYR1 binds to the WW domains of the E3 ubiquitin ligase WWP1 through its PPxY motifs. This interaction triggers K63-linked autoubiquitination and subsequent degradation of WWP1. We furthermore demonstrate that CYYR1 localizes to late endosomal vesicles and directs polyubiquitinated WWP1 toward lysosomal degradation through binding to ANKyrin repeat domain-containing protein 13 A (ANKRD13A). Moreover, we found that CYYR1 expression attenuates breast cancer cell growth in anchorage-dependent and independent colony formation assays in a PPxY-dependent manner. Finally, we highlight that CYYR1 expression is significantly decreased in breast cancer and is associated with beneficial clinical outcome. Taken together our study suggests tumor suppressor properties for CYYR1 through regulation of WWP1 autoubiquitination and lysosomal degradation.
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Affiliation(s)
- Tiphaine Perron
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Mathieu Boissan
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France; APHP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Laboratoire de Biochimie Endocrinienne et Oncologique, Oncobiologie Cellulaire et Moléculaire, Paris, France
| | - Ivan Bièche
- Department of Genetics, Institut Curie, Université Paris Cité, Paris, France
| | - Laura Courtois
- Department of Genetics, Institut Curie, Université Paris Cité, Paris, France
| | - Florent Dingli
- CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France
| | - Damarys Loew
- CurieCoreTech Mass Spectrometry Proteomics, Institut Curie, PSL Research University, Paris, France
| | - Mouna Chouchène
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Sabrina Colasse
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France
| | - Laurence Levy
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
| | - Céline Prunier
- Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
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6
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Mehrtabar E, Khalaji A, Pandeh M, Farhoudian A, Shafiee N, Shafiee A, Ojaghlou F, Mahdavi P, Soleymani-Goloujeh M. Impact of microRNA variants on PI3K/AKT signaling in triple-negative breast cancer: comprehensive review. Med Oncol 2024; 41:222. [PMID: 39120634 DOI: 10.1007/s12032-024-02469-4] [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: 06/10/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024]
Abstract
Breast cancer (BC) is a significant cause of cancer-related mortality, and triple-negative breast cancer (TNBC) is a particularly aggressive subtype associated with high mortality rates, especially among younger females. TNBC poses a considerable clinical challenge due to its aggressive tumor behavior and limited therapeutic options. Aberrations within the PI3K/AKT pathway are prevalent in TNBC and correlate with increased therapeutic intervention resistance and poor outcomes. MicroRNAs (miRs) have emerged as crucial PI3K/AKT pathway regulators influencing various cellular processes involved in TNBC pathogenesis. The levels of miRs, including miR-193, miR-4649-5p, and miR-449a, undergo notable changes in TNBC tumor tissues, emphasizing their significance in cancer biology. This review explored the intricate interplay between miR variants and PI3K/AKT signaling in TNBC. The review focused on the molecular mechanisms underlying miR-mediated dysregulation of this pathway and highlighted specific miRs and their targets. In addition, we explore the clinical implications of miR dysregulation in TNBC, particularly its correlation with TNBC prognosis and therapeutic resistance. Elucidating the roles of miRs in modulating the PI3K/AKT signaling pathway will enhance our understanding of TNBC biology and unveil potential therapeutic targets. This comprehensive review aims to discuss current knowledge and open promising avenues for future research, ultimately facilitating the development of precise and effective treatments for patients with TNBC.
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Affiliation(s)
- Ehsan Mehrtabar
- Advanced Diagnostic and Interventional Radiology Research Center (ADIR), Tehran University of Medical Sciences, Tehran, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojtaba Pandeh
- School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Aram Farhoudian
- School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Nadia Shafiee
- Children's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Atefe Shafiee
- Board-Certified Cardiologist, Rajaie Cardiovascular Medical and Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ojaghlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parinaz Mahdavi
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Soleymani-Goloujeh
- Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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7
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Zhao H, Liu LL, Sun J, Jin L, Xie HB, Li JB, Xu H, Wu DD, Zhuang XL, Peng MS, Guo YJ, Qian WZ, Otecko NO, Sun WJ, Qu LH, He J, Chen ZL, Liu R, Chen CS, Zhang YP. A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression. SCIENCE CHINA. LIFE SCIENCES 2024; 67:765-777. [PMID: 38110796 DOI: 10.1007/s11427-023-2442-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/28/2023] [Indexed: 12/20/2023]
Abstract
Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.
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Affiliation(s)
- Hui Zhao
- State Key Laboratory for Conservation and Utilization of Bio-resource, School of Life Sciences, School of Ecology and Environmental Science, Yunnan University, Kunming, 650091, China.
| | - Lin-Lin Liu
- State Key Laboratory for Conservation and Utilization of Bio-resource, School of Life Sciences, School of Ecology and Environmental Science, Yunnan University, Kunming, 650091, China
- School of Forensic Medicine, Kunming Medical University, Kunming, 650500, China
| | - Jian Sun
- The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Lian Jin
- State Key Laboratory for Conservation and Utilization of Bio-resource, School of Life Sciences, School of Ecology and Environmental Science, Yunnan University, Kunming, 650091, China
| | - Hai-Bing Xie
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Jian-Bo Li
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Hui Xu
- The Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, China
| | - Dong-Dong Wu
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Xiao-Lin Zhuang
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Min-Sheng Peng
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Ya-Jun Guo
- National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering and Antibody, Shanghai, 201203, China
| | - Wei-Zhu Qian
- National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering and Antibody, Shanghai, 201203, China
| | - Newton O Otecko
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Wei-Jie Sun
- State Key Laboratory for Conservation and Utilization of Bio-resource, School of Life Sciences, School of Ecology and Environmental Science, Yunnan University, Kunming, 650091, China
| | - Liang-Hu Qu
- The Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, 510275, China
| | - Jie He
- Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhao-Li Chen
- Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Ce-Shi Chen
- Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
- The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
| | - Ya-Ping Zhang
- State Key Laboratory for Conservation and Utilization of Bio-resource, School of Life Sciences, School of Ecology and Environmental Science, Yunnan University, Kunming, 650091, China.
- State Key Laboratory of Genetic Resources and Evolution, Yunnan Laboratory of Molecular Biology of Domestic Animals, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
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8
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Behera A, Reddy ABM. WWP1 E3 ligase at the crossroads of health and disease. Cell Death Dis 2023; 14:853. [PMID: 38129384 PMCID: PMC10739765 DOI: 10.1038/s41419-023-06380-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023]
Abstract
The E3 ubiquitin ligase WWP1 (WW Domain-containing E3 Ubiquitin Protein Ligase 1) is a member of the HECT (Homologous to the E6-associated protein Carboxyl Terminus) E3 ligase family. It is conserved across several species and plays crucial roles in various physiological processes, including development, cell growth and proliferation, apoptosis, and differentiation. It exerts its functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 plays a role in several human diseases, including cardiac conditions, neurodevelopmental, age-associated osteogenic disorders, infectious diseases, and cancers. In solid tumors, WWP1 plays a dual role as both an oncogene and a tumor suppressor, whereas in hematological malignancies such as AML, it is identified as a dedicated oncogene. Importantly, WWP1 inhibition using small molecule inhibitors such as Indole-3-Carbinol (I3C) and Bortezomib or siRNAs leads to significant suppression of cancer growth and healing of bone fractures, suggesting that WWP1 might serve as a potential therapeutic target for several diseases. In this review, we discuss the evolutionary perspective, structure, and functions of WWP1 and its multilevel regulation by various regulators. We also examine its emerging roles in cancer progression and its therapeutic potential. Finally, we highlight WWP1's role in normal physiology, contribution to pathological conditions, and therapeutic potential for cancer and other diseases.
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Affiliation(s)
- Abhayananda Behera
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
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9
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Fang H, Ren W, Cui Q, Liang H, Yang C, Liu W, Wang X, Liu X, Shi Y, Feng J, Chen C. Integrin β4 promotes DNA damage-related drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/RAC1. eLife 2023; 12:RP88483. [PMID: 37787041 PMCID: PMC10547475 DOI: 10.7554/elife.88483] [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] [Indexed: 10/04/2023] Open
Abstract
Anti-tumor drug resistance is a challenge for human triple-negative breast cancer (TNBC) treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote TNBC cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin β4. Integrin β4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in TNBC. These results indicate that the Integrin β4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in TNBC.
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Affiliation(s)
- Huan Fang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Kunming College of Life Sciences, University of Chinese Academy of SciencesKunming, YunnanChina
| | - Wenlong Ren
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- School of Life Science, University of Science & Technology of ChinaHefeiChina
| | - Qiuxia Cui
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Affiliated Hospital of Guangdong Medical UniversityGuangdongChina
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Huichun Liang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Chuanyu Yang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Wenjing Liu
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Xinye Wang
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
| | - Xue Liu
- Shanghai University of Medicine & Health Sciences Affiliated Sixth People’s Hospital South CampusShanghaiChina
| | - Yujie Shi
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou UniversityZhengzhouChina
| | - Jing Feng
- Shanghai University of Medicine & Health Sciences Affiliated Sixth People’s Hospital South CampusShanghaiChina
- The Second Affiliated Hospital of the Chinese University of Hong Kong (Shenzhen)ShenzhenChina
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangdong ProvinceGuangzhouChina
| | - Ceshi Chen
- Kunming Institute of Zoology, Chinese Academy of SciencesKunming, YunnanChina
- Academy of Biomedical Engineering, Kunming Medical UniversityKunmingChina
- The Third Affiliated Hospital, Kunming Medical UniversityKunmingChina
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10
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Dong Y, Chen Y, Ma G, Cao H. The role of E3 ubiquitin ligases in bone homeostasis and related diseases. Acta Pharm Sin B 2023; 13:3963-3987. [PMID: 37799379 PMCID: PMC10547920 DOI: 10.1016/j.apsb.2023.06.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 10/07/2023] Open
Abstract
The ubiquitin-proteasome system (UPS) dedicates to degrade intracellular proteins to modulate demic homeostasis and functions of organisms. These enzymatic cascades mark and modifies target proteins diversly through covalently binding ubiquitin molecules. In the UPS, E3 ubiquitin ligases are the crucial constituents by the advantage of recognizing and presenting proteins to proteasomes for proteolysis. As the major regulators of protein homeostasis, E3 ligases are indispensable to proper cell manners in diverse systems, and they are well described in physiological bone growth and bone metabolism. Pathologically, classic bone-related diseases such as metabolic bone diseases, arthritis, bone neoplasms and bone metastasis of the tumor, etc., were also depicted in a UPS-dependent manner. Therefore, skeletal system is versatilely regulated by UPS and it is worthy to summarize the underlying mechanism. Furthermore, based on the current status of treatment, normal or pathological osteogenesis and tumorigenesis elaborated in this review highlight the clinical significance of UPS research. As a strategy possibly remedies the limitations of UPS treatment, emerging PROTAC was described comprehensively to illustrate its potential in clinical application. Altogether, the purpose of this review aims to provide more evidence for exploiting novel therapeutic strategies based on UPS for bone associated diseases.
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Affiliation(s)
| | | | - Guixing Ma
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Shenzhen 518055, China
| | - Huiling Cao
- Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Key University Laboratory of Metabolism and Health of Guangdong, Shenzhen 518055, China
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11
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Tian X, Chen Y, Peng Z, Lin Q, Sun A. NEDD4 E3 ubiquitin ligases: promising biomarkers and therapeutic targets for cancer. Biochem Pharmacol 2023:115641. [PMID: 37307883 DOI: 10.1016/j.bcp.2023.115641] [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: 03/15/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/14/2023]
Abstract
Accumulating evidence has demonstrated that NEDD4 E3 ubiquitin ligase family plays a pivotal oncogenic role in a variety of malignancies via mediating ubiquitin dependent degradation processes. Moreover, aberrant expression of NEDD4 E3 ubiquitin ligases is often indicative of cancer progression and correlated with poor prognosis. In this review, we are going to address association of expression of NEDD4 E3 ubiquitin ligases with cancers, the signaling pathways and the molecular mechanisms by which the NEDD4 E3 ubiquitin ligases regulate oncogenesis and progression, and the therapies targeting the NEDD4 E3 ubiquitin ligases. This review provides the systematic and comprehensive summary of the latest research status of E3 ubiquitin ligases in the NEDD4 subfamily, and proposes that NEDD4 family E3 ubiquitin ligases are promising anti-cancer drug targets, aiming to provide research direction for clinical targeting of NEDD4 E3 ubiquitin ligase therapy.
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Affiliation(s)
- Xianyan Tian
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Yifei Chen
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Ziluo Peng
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Qiong Lin
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China
| | - Aiqin Sun
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, China.
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12
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Zhang R, Shi S. The role of NEDD4 related HECT-type E3 ubiquitin ligases in defective autophagy in cancer cells: molecular mechanisms and therapeutic perspectives. Mol Med 2023; 29:34. [PMID: 36918822 PMCID: PMC10015828 DOI: 10.1186/s10020-023-00628-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 02/21/2023] [Indexed: 03/15/2023] Open
Abstract
The homologous to the E6-AP carboxyl terminus (HECT)-type E3 ubiquitin ligases are the selective executers in the protein ubiquitination, playing a vital role in modulation of the protein function and stability. Evidence shows the regulatory role of HECT-type E3 ligases in various steps of the autophagic process. Autophagy is an intracellular digestive and recycling process that controls the cellular hemostasis. Defective autophagy is involved in tumorigenesis and has been detected in various types of cancer cells. A growing body of findings indicates that HECT-type E3 ligases, in particular members of the neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) including NEDD4-1, NEDD4-L, SMURFs, WWPs, and ITCH, play critical roles in dysregulation or dysfunction of autophagy in cancer cells. The present review focuses on NEDD4 E3 ligases involved in defective autophagy in cancer cells and discusses their autophagic function in different cancer cells as well as substrates and the signaling pathways in which they participate, conferring a basis for the cancer treatment through the modulating of these E3 ligases.
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Affiliation(s)
- Rui Zhang
- Department of Thoracic Surgery, The Seventh People's Hospital of Chengdu, Chengdu, 610021, Sichuan, People's Republic of China
| | - Shaoqing Shi
- Scientific Research Laboratory Center, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, People's Republic of China.
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13
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Song MS, Pandolfi PP. The HECT family of E3 ubiquitin ligases and PTEN. Semin Cancer Biol 2022; 85:43-51. [PMID: 34129913 PMCID: PMC8665946 DOI: 10.1016/j.semcancer.2021.06.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/22/2022]
Abstract
Members of the HECT family of E3 ubiquitin ligases have emerged as prominent regulators of PTEN function, subcellular localization and levels. In turn this unfolding regulatory network is allowing for the identification of genes directly involved in both tumorigenesis at large and cancer susceptibility syndromes. While the complexity of this regulatory network is still being unraveled, these new findings are paving the way for novel therapeutic modalities for cancer prevention and therapy as well as for other diseases. Here we will review the signal transduction and therapeutic implications of the cross-talk between HECT family members and PTEN.
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Affiliation(s)
- Min Sup Song
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.
| | - Pier Paolo Pandolfi
- Renown Institute for Cancer, Nevada System of Higher Education, Reno, NV89502, USA.
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14
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Wang K, Liu J, Li YL, Li JP, Zhang R. Ubiquitination/de-ubiquitination: A promising therapeutic target for PTEN reactivation in cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188723. [DOI: 10.1016/j.bbcan.2022.188723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 02/07/2023]
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15
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Zhang H, Li X, Liu J, Lin X, Pei L, Boyce BF, Xing L. Proteasome inhibition-enhanced fracture repair is associated with increased mesenchymal progenitor cells in mice. PLoS One 2022; 17:e0263839. [PMID: 35213543 PMCID: PMC8880819 DOI: 10.1371/journal.pone.0263839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/27/2022] [Indexed: 11/19/2022] Open
Abstract
The ubiquitin/proteasome system controls the stability of Runx2 and JunB, proteins essential for differentiation of mesenchymal progenitor/stem cells (MPCs) to osteoblasts. Local administration of proteasome inhibitor enhances bone fracture healing by accelerating endochondral ossification. However, if a short-term administration of proteasome inhibitor enhances fracture repair and potential mechanisms involved have yet to be exploited. We hypothesize that injury activates the ubiquitin/proteasome system in callus, leading to elevated protein ubiquitination and degradation, decreased MPCs, and impaired fracture healing, which can be prevented by a short-term of proteasome inhibition. We used a tibial fracture model in Nestin-GFP reporter mice, in which a subgroup of MPCs are labeled by Nestin-GFP, to test our hypothesis. We found increased expression of ubiquitin E3 ligases and ubiquitinated proteins in callus tissues at the early phase of fracture repair. Proteasome inhibitor Bortezomib, given soon after fracture, enhanced fracture repair, which is accompanied by increased callus Nestin-GFP+ cells and their proliferation, and the expression of osteoblast-associated genes and Runx2 and JunB proteins. Thus, early treatment of fractures with Bortezomib could enhance the fracture repair by increasing the number and proliferation of MPCs.
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Affiliation(s)
- Hengwei Zhang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Xing Li
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Jiatong Liu
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Xi Lin
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Lingpeng Pei
- Key Laboratory of Ethnomedicine, Minzu University of China, Beijing, China
| | - Brendan F. Boyce
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Lianping Xing
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, United States of America
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York, United States of America
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16
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Zimmermann RC, Sardiu ME, Manton CA, Miah MS, Banks CAS, Adams MK, Koestler DC, Hurst DR, Edmonds MD, Washburn MP, Welch DR. Perturbation of BRMS1 interactome reveals pathways that impact metastasis. PLoS One 2021; 16:e0259128. [PMID: 34788285 PMCID: PMC8598058 DOI: 10.1371/journal.pone.0259128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/12/2021] [Indexed: 11/25/2022] Open
Abstract
Breast Cancer Metastasis Suppressor 1 (BRMS1) expression is associated with longer patient survival in multiple cancer types. Understanding BRMS1 functionality will provide insights into both mechanism of action and will enhance potential therapeutic development. In this study, we confirmed that the C-terminus of BRMS1 is critical for metastasis suppression and hypothesized that critical protein interactions in this region would explain its function. Phosphorylation status at S237 regulates BRMS1 protein interactions related to a variety of biological processes, phenotypes [cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1)], and metastasis [(e.g., TCF2 and POLE2)]. Presence of S237 also directly decreased MDA-MB-231 breast carcinoma migration in vitro and metastases in vivo. The results add significantly to our understanding of how BRMS1 interactions with Sin3/HDAC complexes regulate metastasis and expand insights into BRMS1's molecular role, as they demonstrate BRMS1 C-terminus involvement in distinct protein-protein interactions.
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Affiliation(s)
- Rosalyn C. Zimmermann
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, KS, United States of America
| | - Mihaela E. Sardiu
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
- Department of Biostatistics and Data Science, The Kansas University Medical Center, Kansas City, KS, United States of America
- The University of Kansas Cancer Center, Kansas City, KS, United States of America
| | - Christa A. Manton
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, KS, United States of America
- Pathology Department, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- Department of Biology, Baker University, Baldwin City, KS, United States of America
| | - Md. Sayem Miah
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
- Department of Biochemistry and Molecular Biology, University of Arkansas for Health Sciences, Little Rock, AR, United States of America
| | - Charles A. S. Banks
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
| | - Mark K. Adams
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
| | - Devin C. Koestler
- Department of Biostatistics and Data Science, The Kansas University Medical Center, Kansas City, KS, United States of America
- The University of Kansas Cancer Center, Kansas City, KS, United States of America
| | - Douglas R. Hurst
- Pathology Department, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Mick D. Edmonds
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Michael P. Washburn
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, KS, United States of America
- Stowers Institute for Medical Research, Kansas City, Missouri, United States of America
- The University of Kansas Cancer Center, Kansas City, KS, United States of America
| | - Danny R. Welch
- Department of Cancer Biology, The Kansas University Medical Center, Kansas City, KS, United States of America
- The University of Kansas Cancer Center, Kansas City, KS, United States of America
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17
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Kuang L, Jiang Y, Li C, Jiang Y. WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein. Front Cell Dev Biol 2021; 9:757493. [PMID: 34712671 PMCID: PMC8545989 DOI: 10.3389/fcell.2021.757493] [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: 08/12/2021] [Accepted: 09/21/2021] [Indexed: 11/13/2022] Open
Abstract
WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of C2-WW-HECT E3 ligase family. Although it may execute carcinostatic actions in some scenarios, WWP1 functions as an oncoprotein under most circumstances. Here, we comprehensively review reports on regulation of WWP1 and its roles in tumorigenesis. We summarize the WWP1-mediated ubiquitinations of diverse proteins and the signaling pathways they involved, as well as the mechanisms how they affect cancer formation and progression. According to our analysis of database, in combination with previous reports, we come to a conclusion that WWP1 expression is augmented in various cancers. Gene amplification, as well as expression regulation mediated by molecules such as non-coding RNAs, may account for the increased mRNA level of WWP1. Regulation of enzymatic activity is another important facet to upregulate WWP1-mediated ubiquitinations. Based on the published data, we conclude that WWP1 employs interactions between multiple domains to autoinhibit its polyubiquitination activity in a steady state. Association of some substrates can partially release certain autoinhibition-related domains and make WWP1 have a moderate activity of polyubiquitination. Some cancer-related mutations can fully disrupt the inhibitory interactions and make WWP1 hyperactive. High expression level or hyperactivation of WWP1 may abnormally enhance polyubiquitinations of some oncoproteins or tumor suppressors, such as ΔNp63α, PTEN and p27, and ultimately promote cell proliferation, survival, migration and invasion in tumorigenesis. Given the dysregulation and oncogenic functions of WWP1 in some cancer types, it is promising to explore some therapeutic inhibitors to tune down its activity.
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Affiliation(s)
- Linghan Kuang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Yunhui Jiang
- Pathology Department, The Second People's Hospital of Jingmen, Jingmen, China
| | - Chenghua Li
- Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China
| | - Yongmei Jiang
- Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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18
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Delvecchio VS, Fierro C, Giovannini S, Melino G, Bernassola F. Emerging roles of the HECT-type E3 ubiquitin ligases in hematological malignancies. Discov Oncol 2021; 12:39. [PMID: 35201500 PMCID: PMC8777521 DOI: 10.1007/s12672-021-00435-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/13/2021] [Indexed: 02/07/2023] Open
Abstract
Ubiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.
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Affiliation(s)
- Vincenza Simona Delvecchio
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| | - Claudia Fierro
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| | - Sara Giovannini
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| | - Gerry Melino
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
| | - Francesca Bernassola
- Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
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19
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Song Y, Song X, Zhang D, Yang Y, Wang L, Song L. An HECT domain ubiquitin ligase CgWWP1 regulates granulocytes proliferation in oyster Crassostrea gigas. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 123:104148. [PMID: 34097916 DOI: 10.1016/j.dci.2021.104148] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 06/12/2023]
Abstract
Ubiquitination is involved in the regulation of granulocyte proliferation in vertebrate, and E3 ubiquitin ligase WWP1 has been reported to play an essential role in this process. In the present study, an HECT type E3 ubiquitin ligase (CgWWP1) was identified from oyster Crassostrea gigas, which contained a N-terminal C2 domain, four WW domains, and a C-terminal HECT domain. CgWWP1 was able to bind the activated ubiquitin (Ub) and formed CgWWP1-Ub complex in vitro. The mRNA transcripts of CgWWP1 were expressed in granulocytes, semi-granulocytes and agranulocytes, with the highest expression level in granulocytes. The expressions of potential granulocyte markers CgSOX11 (0.18-fold, p < 0.05) and CgAATase (0.2-fold, p < 0.01) in haemocytes were significantly down-regulated at 24 h after the treatment with Indole-3-carbinol (I3C), a WWP1 inhibitor. The proportions of EdU+ granulocytes reduced significantly at 12 h (8.1% ± 1.4%) and 24 h (9.7% ± 2.8%) after I3C treatment, which were significantly lower than that in the sterile seawater treatment (SW) group at 12 h (15.8% ± 4.2%) and 24 h (17.6% ± 0.8%), respectively. Meanwhile, the green EdU signals observed by confocal scanning microscopy in granulocytes of oysters treated by I3C became weaker compared to that in the SW group. These results indicated that CgWWP1 was involved in the regulation of granulocyte proliferation as a ubiquitin-protein ligase.
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Affiliation(s)
- Ying Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Xiaorui Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Dan Zhang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Ying Yang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Zhuhai, 519000, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Southern Laboratory of Ocean Science and Engineering (Guangdong, Zhuhai), Zhuhai, 519000, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China.
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20
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Zhao H, Zhang J, Fu X, Mao D, Qi X, Liang S, Meng G, Song Z, Yang R, Guo Z, Tong B, Sun M, Zuo B, Li G. Integrated bioinformatics analysis of the NEDD4 family reveals a prognostic value of NEDD4L in clear-cell renal cell cancer. PeerJ 2021; 9:e11880. [PMID: 34458018 PMCID: PMC8378337 DOI: 10.7717/peerj.11880] [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: 02/03/2021] [Accepted: 07/07/2021] [Indexed: 12/20/2022] Open
Abstract
The members of the Nedd4-like E3 family participate in various biological processes. However, their role in clear cell renal cell carcinoma (ccRCC) is not clear. This study systematically analyzed the Nedd4-like E3 family members in ccRCC data sets from multiple publicly available databases. NEDD4L was identified as the only NEDD4 family member differentially expressed in ccRCC compared with normal samples. Bioinformatics tools were used to characterize the function of NEDD4L in ccRCC. It indicated that NEDD4L might regulate cellular energy metabolism by co-expression analysis, and subsequent gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A prognostic model developed by the LASSO Cox regression method showed a relatively good predictive value in training and testing data sets. The result revealed that NEDD4L was associated with biosynthesis and metabolism of ccRCC. Since NEDD4L is downregulated and dysregulation of metabolism is involved in tumor progression, NEDD4L might be a potential therapeutic target in ccRCC.
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Affiliation(s)
- Hui Zhao
- Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, China.,Department of Urology, China Rehabilitation Research Centre, Rehabilitation School of Capital Medical University, Beijing, China
| | - Junjun Zhang
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Xiaoliang Fu
- Department of Urology, The Second Affiliated Hospital of Air Force Medical University, Xian, China
| | - Dongdong Mao
- Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xuesen Qi
- Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Shuai Liang
- Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Gang Meng
- Department of Urology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zewen Song
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Ru Yang
- Henan Key Laboratory of Neurorestoratology, The First Affliated Hospital of Xinxiang Medical University, Weihui, China
| | - Zhenni Guo
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Binghua Tong
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Meiqing Sun
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China
| | - Baile Zuo
- Tumor Molecular Immunology and Immunotherapy Laboratory, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Guoyin Li
- College of Life Science and Agronomy, Zhoukou Normal University, Zhoukou, China.,Academy of Medical Science, Zhengzhou University, Zhengzhou, China
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21
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Wang X, Bi Y, Liu X, Liu L, Hao M, Tian M, Shang J. High Expression of WWP1 Associates with Tumor Progression in Papillary Thyroid Cancer. Cancer Biother Radiopharm 2021; 37:313-323. [PMID: 34388030 DOI: 10.1089/cbr.2020.4148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background: WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is increased in several kinds of carcinomas, but the influence of WWP1 in papillary thyroid cancer (PTC) is not well understood. Materials and Methods: The expression of WWP1 in PTC tissues and cells is detected by real-time reverse transcription PCR. The biological role of WWP1 on PTC cell growth, apoptosis, migration, and invasion ability was assessed with the Cell Counting Kit-8, colony forming, flow cytometry, wound healing, and transwell assays, respectively. Results: The expression of WWP1 mRNA and protein is increased in PTC tissue samples and cells. There is closely correlation between the up expression of WWP1 and clinical parameters, such as tumor size, TNM, and distant metastasis. Knockdown of WWP1 blocks cell proliferation, migration, and invasion, causes cell cycle arrest, and induces apoptosis in PTC cells. Knockdown of WWP1 increases PTEN level and reduces p-PI3K and p-Akt level in PTC cells. Conclusions: Knockdown of WWP1 suppressed cell proliferation, migration, and invasion of PTC cell by downregulating the expression of p-PI3K and p-Akt, contributing to their understanding the pathogenesis of PTC.
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Affiliation(s)
- Xiaofeng Wang
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
| | - Yanqing Bi
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
| | - Xiaofang Liu
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
| | - Lili Liu
- Department of Pathology, Dongying People's Hospital, Dongying, P.R. China
| | - Min Hao
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
| | - Mengzi Tian
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
| | - Jian Shang
- Department of Breast and Thyroid Surgery, Dongying People's Hospital, Dongying, P.R. China
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Lv B, Stuck MW, Desai PB, Cabrera OA, Pazour GJ. E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened. J Cell Biol 2021; 220:212435. [PMID: 34161574 PMCID: PMC8236919 DOI: 10.1083/jcb.202010177] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 05/01/2021] [Accepted: 06/01/2021] [Indexed: 12/26/2022] Open
Abstract
The Hedgehog pathway, critical to vertebrate development, is organized in primary cilia. Activation of signaling causes the Hedgehog receptor Ptch1 to exit cilia, allowing a second receptor, Smo, to accumulate in cilia and activate the downstream steps of the pathway. Mechanisms regulating the dynamics of these receptors are unknown, but the ubiquitination of Smo regulates its interaction with the intraflagellar transport system to control ciliary levels. A focused screen of ubiquitin-related genes identified nine required for maintaining low ciliary Smo at the basal state. These included cytoplasmic E3s (Arih2, Mgrn1, and Maea), a ciliary localized E3 (Wwp1), a ciliary localized E2 (Ube2l3), a deubiquitinase (Bap1), and three adaptors (Kctd5, Skp1a, and Skp2). The ciliary E3, Wwp1, binds Ptch1 and localizes to cilia at the basal state. Activation of signaling removes both Ptch1 and Wwp1 from cilia, thus providing an elegant mechanism for Ptch1 to regulate ciliary Smo levels.
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Affiliation(s)
- Bo Lv
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Michael W Stuck
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Paurav B Desai
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Oscar A Cabrera
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Gregory J Pazour
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
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23
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The emerging role of WWP1 in cancer development and progression. Cell Death Discov 2021; 7:163. [PMID: 34226507 PMCID: PMC8257788 DOI: 10.1038/s41420-021-00532-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/08/2021] [Accepted: 05/23/2021] [Indexed: 12/16/2022] Open
Abstract
Emerging evidence demonstrates that WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) participates into carcinogenesis and tumor progression. In this review article, we will describe the association between dysregulated WWP1 expression and clinical features of cancer patients. Moreover, we summarize the both oncogenic and tumor suppressive functions of WWP1 in a variety of human cancers. Furthermore, we briefly describe the downstream substrates of WWP1 and its upstream factors to regulate the expression of WWP1. Notably, targeting WWP1 by its inhibitors or natural compounds is potentially useful for treating human malignancies. Finally, we provide the perspectives regarding WWP1 in cancer development and therapies. We hope this review can stimulate the research to improve our understanding of WWP1-mediated tumorigenesis and accelerate the discovery of novel therapeutic strategies via targeting WWP1 expression in cancers.
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24
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Mathieu NA, Levin RH, Spratt DE. Exploring the Roles of HERC2 and the NEDD4L HECT E3 Ubiquitin Ligase Subfamily in p53 Signaling and the DNA Damage Response. Front Oncol 2021; 11:659049. [PMID: 33869064 PMCID: PMC8044464 DOI: 10.3389/fonc.2021.659049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/16/2021] [Indexed: 12/27/2022] Open
Abstract
Cellular homeostasis is governed by the precise expression of genes that control the translation, localization, and termination of proteins. Oftentimes, environmental and biological factors can introduce mutations into the genetic framework of cells during their growth and division, and these genetic abnormalities can result in malignant transformations caused by protein malfunction. For example, p53 is a prominent tumor suppressor protein that is capable of undergoing more than 300 posttranslational modifications (PTMs) and is involved with controlling apoptotic signaling, transcription, and the DNA damage response (DDR). In this review, we focus on the molecular mechanisms and interactions that occur between p53, the HECT E3 ubiquitin ligases WWP1, SMURF1, HECW1 and HERC2, and other oncogenic proteins in the cell to explore how irregular HECT-p53 interactions can induce tumorigenesis.
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Affiliation(s)
- Nicholas A Mathieu
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, MA, United States
| | - Rafael H Levin
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, MA, United States
| | - Donald E Spratt
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, MA, United States
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25
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CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway. Mol Cancer 2021; 20:43. [PMID: 33648498 PMCID: PMC7919093 DOI: 10.1186/s12943-021-01332-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). METHODS TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. RESULTS CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. CONCLUSIONS CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.
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26
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Selvaraj J, Rekha UV, Jh SF, Sivabalan V, Ponnulakshmi R, Priya VV, Kullappan M, Sreekandan RN, Mohan SK. Molecular docking data of E3 ubiquitin-protein ligase WWP1 with compounds from a medicinal plant Justicia adhatoda L. Bioinformation 2021; 17:162-166. [PMID: 34393432 PMCID: PMC8340721 DOI: 10.6026/97320630017162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 11/23/2022] Open
Abstract
It is known that E3 ubiquitin-protein ligase WWP1 is linked to oral cancer. Therefore, it is of interest to document molecular docking data of E3 ubiquitin-protein ligase WWP1 with compounds ((Stigmasterol, Pyrazinamide, Vasicinone and Ethambutol)) from a medicinal plant Justicia adhatoda L for further consideration.
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Affiliation(s)
- Jayaraman Selvaraj
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
| | - Umapathy Vidhya Rekha
- Department of Public Health Dentistry, Sree Balaji Dental College and Hospital, Pallikaranai,Chennai-600 100, India
| | - Shazia Fathima Jh
- Department of Oral and Maxillofacial Pathology, Ragas Dental College and Hospitals, Chennai, India
| | - Venkatacalam Sivabalan
- Department of Biochemistry, KSR Institute of Dental Sciences and Research, Thiruchengodu-637215, India
| | - Rajagopal Ponnulakshmi
- Central Research Laboratory,Meenakshi Academy of Higher Education and Research (Deemed to be University), Chennai-600 078, India
| | - Veeraraghavan Vishnu Priya
- Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
| | - Malathi Kullappan
- Department of Research,Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai - 600 123, India
| | - Radhika Nalinakumari Sreekandan
- Department of Clinical Skills & Simulation, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai - 600 123, India
| | - Surapaneni Krishna Mohan
- Department of Biochemistry and Department of Clinical Skills & Simulation, Department of Research, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai - 600 123, India
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Sinha A, Iyengar PV, ten Dijke P. E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression. Int J Mol Sci 2021; 22:E476. [PMID: 33418880 PMCID: PMC7825147 DOI: 10.3390/ijms22020476] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023] Open
Abstract
Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.
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Affiliation(s)
| | | | - Peter ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.S.); (P.V.I.)
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28
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Rodríguez-Alonso A, Casas-Pais A, Roca-Lema D, Graña B, Romay G, Figueroa A. Regulation of Epithelial-Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer. Cancers (Basel) 2020; 12:cancers12113093. [PMID: 33114139 PMCID: PMC7690828 DOI: 10.3390/cancers12113093] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/08/2020] [Accepted: 10/22/2020] [Indexed: 12/22/2022] Open
Abstract
The epithelial-mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer.
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Affiliation(s)
- Andrea Rodríguez-Alonso
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (A.R.-A.); (A.C.-P.); (D.R.-L.); (G.R.)
| | - Alba Casas-Pais
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (A.R.-A.); (A.C.-P.); (D.R.-L.); (G.R.)
| | - Daniel Roca-Lema
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (A.R.-A.); (A.C.-P.); (D.R.-L.); (G.R.)
| | - Begoña Graña
- Clinical Oncology Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain;
| | - Gabriela Romay
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (A.R.-A.); (A.C.-P.); (D.R.-L.); (G.R.)
| | - Angélica Figueroa
- Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain; (A.R.-A.); (A.C.-P.); (D.R.-L.); (G.R.)
- Correspondence:
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29
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Yang C, Wu J, Liu X, Wang Y, Liu B, Chen X, Wu X, Yan D, Han L, Liu S, Shan L, Shang Y. Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis. Cancer Res 2020; 80:4114-4128. [PMID: 32651256 DOI: 10.1158/0008-5472.can-20-0493] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/26/2020] [Accepted: 07/07/2020] [Indexed: 11/16/2022]
Abstract
Copy number gain in chromosome 8q21 is frequently detected in breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. ZNF704 acted as a transcriptional repressor and interacted with the transcriptional corepressor SIN3A complex. Genome-wide interrogation of transcriptional targets revealed that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of the circadian clock. Overexpression of ZNF704 prolonged the period and dampened the amplitude of the circadian clock. ZNF704 promoted the proliferation and invasion of breast cancer cells in vitro and accelerated the growth and metastasis of breast cancer in vivo. Consistently, the level of ZNF704 expression inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlated with advanced histologic grades, lymph node positivity, and poor prognosis of patients with breast cancer, especially those with HER2+ and basal-like subtypes. These results indicate that ZNF704 is an important regulator of the circadian clock and a potential driver for breast carcinogenesis. SIGNIFICANCE: This study indicates that ZNF704 could be a potential oncogenic factor, disrupting circadian rhythm of breast cancer cells and contributing to breast carcinogenesis.
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Affiliation(s)
- Chao Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Jiajing Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xinhua Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Yue Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Beibei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xing Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Xiaodi Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Dong Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lulu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Shumeng Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lin Shan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yongfeng Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China. .,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China.,Laboratory of Cancer Epigenetics, Chinese Academy of Medical Sciences Beijing, China
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30
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Chen L, Liu S, Tao Y. Regulating tumor suppressor genes: post-translational modifications. Signal Transduct Target Ther 2020; 5:90. [PMID: 32532965 PMCID: PMC7293209 DOI: 10.1038/s41392-020-0196-9] [Citation(s) in RCA: 236] [Impact Index Per Article: 47.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 05/19/2020] [Accepted: 05/24/2020] [Indexed: 01/10/2023] Open
Abstract
Tumor suppressor genes cooperate with each other in tumors. Three important tumor suppressor proteins, retinoblastoma (Rb), p53, phosphatase, and tensin homolog deleted on chromosome ten (PTEN) are functionally associated and they regulated by post-translational modification (PTMs) as well. PTMs include phosphorylation, SUMOylation, acetylation, and other novel modifications becoming growing appreciated. Because most of PTMs are reversible, normal cells use them as a switch to control the state of cells being the resting or proliferating, and PTMs also involve in cell survival and cell cycle, which may lead to abnormal proliferation and tumorigenesis. Although a lot of studies focus on the importance of each kind of PTM, further discoveries shows that tumor suppressor genes (TSGs) form a complex "network" by the interaction of modification. Recently, there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers. We here review the necessity, characteristics, and mechanisms of each kind of post-translational modification on Rb, p53, PTEN, and its influence on the precise and selective function. We also discuss the current antitumoral therapies of Rb, p53 and PTEN as predictive, prognostic, and therapeutic target in cancer.
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Affiliation(s)
- Ling Chen
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute, Central South University, 410078, Changsha, Hunan, China.
- Hunan Key Laboratory of Early Diagnosis and Precision Therapy, Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, 410011, Changsha, China.
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Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP. WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition. N Engl J Med 2020; 382:2103-2116. [PMID: 32459922 PMCID: PMC7839065 DOI: 10.1056/nejmoa1914919] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. METHODS In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants. RESULTS The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. CONCLUSIONS In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
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Affiliation(s)
- Yu-Ru Lee
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Lamis Yehia
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Takahiro Kishikawa
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Ying Ni
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Brandie Leach
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Jinfang Zhang
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Nivedita Panch
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Jing Liu
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Wenyi Wei
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Charis Eng
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
| | - Pier Paolo Pandolfi
- From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.)
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32
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Wang Y, Argiles-Castillo D, Kane EI, Zhou A, Spratt DE. HECT E3 ubiquitin ligases - emerging insights into their biological roles and disease relevance. J Cell Sci 2020; 133:133/7/jcs228072. [PMID: 32265230 DOI: 10.1242/jcs.228072] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases play a critical role in various cellular pathways, including but not limited to protein trafficking, subcellular localization, innate immune response, viral infections, DNA damage responses and apoptosis. To date, 28 HECT E3 ubiquitin ligases have been identified in humans, and recent studies have begun to reveal how these enzymes control various cellular pathways by catalyzing the post-translational attachment of ubiquitin to their respective substrates. New studies have identified substrates and/or interactors with different members of the HECT E3 ubiquitin ligase family, particularly for E6AP and members of the neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) family. However, there still remains many unanswered questions about the specific roles that each of the HECT E3 ubiquitin ligases have in maintaining cellular homeostasis. The present Review discusses our current understanding on the biological roles of the HECT E3 ubiquitin ligases in the cell and how they contribute to disease development. Expanded investigations on the molecular basis for how and why the HECT E3 ubiquitin ligases recognize and regulate their intracellular substrates will help to clarify the biochemical mechanisms employed by these important enzymes in ubiquitin biology.
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Affiliation(s)
- Yaya Wang
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054.,Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Diana Argiles-Castillo
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Emma I Kane
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
| | - Anning Zhou
- College of Chemistry and Chemical Engineering, Xi'an University of Science and Technology, Xi'an, Shanxi, China 710054
| | - Donald E Spratt
- Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, 950 Main St., Worcester, MA 01610, USA
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33
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Jiang Q, Li F, Cheng Z, Kong Y, Chen C. The role of E3 ubiquitin ligase HECTD3 in cancer and beyond. Cell Mol Life Sci 2020; 77:1483-1495. [PMID: 31637449 PMCID: PMC11105068 DOI: 10.1007/s00018-019-03339-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 10/02/2019] [Accepted: 10/07/2019] [Indexed: 02/07/2023]
Abstract
Ubiquitin modification plays significant roles in protein fate determination, signaling transduction, and cellular processes. Over the past 2 decades, the number of studies on ubiquitination has demonstrated explosive growth. E3 ubiquitin ligases are the key enzymes that determine the substrate specificity and are involved in cancer. Several recent studies shed light on the functions and mechanisms of HECTD3 E3 ubiquitin ligase. This review describes the progress in the recent studies of HECTD3 in cancer and other diseases. We propose that HECTD3 is a potential biomarker and a therapeutic target, and discuss the future directions for HECTD3 investigations.
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Affiliation(s)
- Qiuyun Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650204, China
| | - Fubing Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Zhuo Cheng
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650204, China
| | - Yanjie Kong
- Institute of Translation Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
- Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, 650204, China.
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
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34
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Hoshino S, Kobayashi M, Tagawa R, Konno R, Abe T, Furuya K, Miura K, Wakasawa H, Okita N, Sudo Y, Mizunoe Y, Nakagawa Y, Nakamura T, Kawabe H, Higami Y. WWP1 knockout in mice exacerbates obesity-related phenotypes in white adipose tissue but improves whole-body glucose metabolism. FEBS Open Bio 2020; 10:306-315. [PMID: 31965758 PMCID: PMC7050250 DOI: 10.1002/2211-5463.12795] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/27/2019] [Accepted: 01/16/2020] [Indexed: 12/31/2022] Open
Abstract
White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT-type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high-fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole-body glucose metabolism.
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Affiliation(s)
- Shunsuke Hoshino
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Masaki Kobayashi
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Ryoma Tagawa
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Ryutaro Konno
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Takuro Abe
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Kazuhiro Furuya
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Kumi Miura
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Hiroki Wakasawa
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Naoyuki Okita
- Division of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-onoda, Japan
| | - Yuka Sudo
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Yuhei Mizunoe
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takeshi Nakamura
- Division of Biosignaling, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
| | - Hiroshi Kawabe
- Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.,Division of Pathogenic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.,Department of Gerontology, Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Japan
| | - Yoshikazu Higami
- Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
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35
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Gâtel P, Piechaczyk M, Bossis G. Ubiquitin, SUMO, and Nedd8 as Therapeutic Targets in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1233:29-54. [PMID: 32274752 DOI: 10.1007/978-3-030-38266-7_2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ubiquitin defines a family of approximately 20 peptidic posttranslational modifiers collectively called the Ubiquitin-like (UbLs). They are conjugated to thousands of proteins, modifying their function and fate in many ways. Dysregulation of these modifications has been implicated in a variety of pathologies, in particular cancer. Ubiquitin, SUMO (-1 to -3), and Nedd8 are the best-characterized UbLs. They have been involved in the regulation of the activity and/or the stability of diverse components of various oncogenic or tumor suppressor pathways. Moreover, the dysregulation of enzymes responsible for their conjugation/deconjugation has also been associated with tumorigenesis and cancer resistance to therapies. The UbL system therefore constitutes an attractive target for developing novel anticancer therapeutic strategies. Here, we review the roles and dysregulations of Ubiquitin, SUMO, and Nedd8 pathways in tumorigenesis, as well as recent advances in the identification of small molecules targeting their conjugating machineries for potential application in the fight against cancer.
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Affiliation(s)
- Pierre Gâtel
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France
| | - Marc Piechaczyk
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France
| | - Guillaume Bossis
- Equipe Labellisée Ligue Contre le Cancer, IGMM, Univ Montpellier, CNRS, Montpellier, France.
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36
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Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, Chen H, Ishikawa T, Chiang SY, Katon J, Zhang Y, Shulga YV, Bester AC, Fung J, Monteleone E, Wan L, Shen C, Hsu CH, Papa A, Clohessy JG, Teruya-Feldstein J, Jain S, Wu H, Matesic L, Chen RH, Wei W, Pandolfi PP. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 2019; 364:364/6441/eaau0159. [PMID: 31097636 DOI: 10.1126/science.aau0159] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 10/30/2018] [Accepted: 03/27/2019] [Indexed: 12/18/2022]
Abstract
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.
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Affiliation(s)
- Yu-Ru Lee
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ming Chen
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jonathan D Lee
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jinfang Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Shu-Yu Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan
| | - Tian-Min Fu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.,Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115
| | - Hao Chen
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.,Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Tomoki Ishikawa
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Shang-Yin Chiang
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan
| | - Jesse Katon
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yang Zhang
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yulia V Shulga
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Assaf C Bester
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jacqueline Fung
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Emanuele Monteleone
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Molecular Biotechnology and Health Sciences, and GenoBiToUS, Genomics and Bioinformatics Service, University of Turin, Turin, Italy
| | - Lixin Wan
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.,Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Chen Shen
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.,Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115
| | - Chih-Hung Hsu
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.,Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.,Department of Public Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China
| | - Antonella Papa
- Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia
| | - John G Clohessy
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.,Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
| | - Julie Teruya-Feldstein
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Suresh Jain
- Intonation Research Laboratories, Hyderabad, India
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.,Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115
| | - Lydia Matesic
- Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Ruey-Hwa Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Pier Paolo Pandolfi
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA. .,Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Bernassola F, Chillemi G, Melino G. HECT-Type E3 Ubiquitin Ligases in Cancer. Trends Biochem Sci 2019; 44:1057-1075. [DOI: 10.1016/j.tibs.2019.08.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/13/2019] [Accepted: 08/23/2019] [Indexed: 12/30/2022]
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Melino G, Cecconi F, Pelicci PG, Mak TW, Bernassola F. Emerging roles of HECT-type E3 ubiquitin ligases in autophagy regulation. Mol Oncol 2019; 13:2033-2048. [PMID: 31441992 PMCID: PMC6763782 DOI: 10.1002/1878-0261.12567] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/19/2019] [Accepted: 08/22/2019] [Indexed: 12/20/2022] Open
Abstract
Autophagy is a conserved self-eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post-translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus-type E3 ubiquitin ligases in autophagy control.
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Affiliation(s)
- Gerry Melino
- Department of Experimental MedicineTORUniversity of Rome “Tor Vergata”Italy
- Medical Research Council, Toxicology UnitUniversity of CambridgeUK
| | - Francesco Cecconi
- Cell Stress and Survival UnitDanish Cancer Society Research CenterCopenhagenDenmark
- Department of BiologyTor Vergata University of RomeItaly
- Department of Pediatric Hematology and OncologyIRCCS Bambino Gesù Children's HospitalRomeItaly
| | - Pier Giuseppe Pelicci
- Department of Experimental OncologyIEO, European Institute of Oncology IRCCSMilanItaly
- Department of Oncology and Haemato‐OncologyMilan UniversityItaly
| | - Tak Wah Mak
- The Campbell Family Institute for Breast Cancer ResearchOntario Cancer InstitutePrincess Margaret HospitalTorontoONCanada
| | - Francesca Bernassola
- Department of Experimental MedicineTORUniversity of Rome “Tor Vergata”Italy
- Department of Experimental OncologyIEO, European Institute of Oncology IRCCSMilanItaly
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Wang Z, Liu Z, Chen X, Li J, Yao W, Huang S, Gu A, Lei QY, Mao Y, Wen W. A multi-lock inhibitory mechanism for fine-tuning enzyme activities of the HECT family E3 ligases. Nat Commun 2019; 10:3162. [PMID: 31320636 PMCID: PMC6639328 DOI: 10.1038/s41467-019-11224-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 07/01/2019] [Indexed: 12/12/2022] Open
Abstract
HECT E3 ligases control the degradation and functioning of numerous oncogenic/tumor-suppressive factors and signaling proteins, and their activities must be tightly regulated to prevent cancers and other diseases. Here we show that the Nedd4 family HECT E3 WWP1 adopts an autoinhibited state, in which its multiple WW domains sequester HECT using a multi-lock mechanism. Removing WW2 or WW34 led to a partial activation of WWP1. The structure of fully inhibited WWP1 reveals that many WWP1 mutations identified in cancer patients result in a partially active state with increased E3 ligase activity, and the WWP1 mutants likely promote cell migration by enhancement of ∆Np63α degradation. We further demonstrate that WWP2 and Itch utilize a highly similar multi-lock autoinhibition mechanism as that utilized by WWP1, whereas Nedd4/4 L and Smurf2 utilize a slightly variant version. Overall, these results reveal versatile autoinhibitory mechanisms that fine-tune the ligase activities of the HECT family enzymes. HECT type E3 ligases are key regulators of cell growth and proliferation. Here the authors present the crystal structures of the Nedd4 family E3 ligase WWP1 in a closed and semi-open state and in combination with mutagenesis experiments identify a multi-lock regulatory mechanism that allows the fine-tuning of activities of Nedd4 family E3 ligases.
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Affiliation(s)
- Zhen Wang
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ziheng Liu
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xing Chen
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jingyu Li
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Weiyi Yao
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Shijing Huang
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Aihong Gu
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qun-Ying Lei
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Fudan University, Shanghai, 200032, China
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Wenyu Wen
- Department of Neurosurgery, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Tecalco-Cruz AC, Ramírez-Jarquín JO, Cruz-Ramos E. Estrogen Receptor Alpha and its Ubiquitination in Breast Cancer Cells. Curr Drug Targets 2019; 20:690-704. [DOI: 10.2174/1389450119666181015114041] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/09/2018] [Accepted: 10/09/2018] [Indexed: 12/23/2022]
Abstract
More than 70% of all breast cancer cases are estrogen receptor alpha-positive (ERα). ERα is a member of the nuclear receptor family, and its activity is implicated in the gene transcription linked to the proliferation of breast cancer cells, as well as in extranuclear signaling pathways related to the development of resistance to endocrine therapy. Protein-protein interactions and posttranslational modifications of ERα underlie critical mechanisms that modulate its activity. In this review, the relationship between ERα and ubiquitin protein (Ub), was investigated in the context of breast cancer cells. Interestingly, Ub can bind covalently or non-covalently to ERα resulting in either a proteolytic or non-proteolytic fate for this receptor. Thereby, Ub-dependent molecular pathways that modulate ERα signaling may play a central role in breast cancer progression, and consequently, present critical targets for treatment of this disease.
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Affiliation(s)
- Angeles C. Tecalco-Cruz
- Instituto de Investigaciones Biomedicas. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
| | - Josué O. Ramírez-Jarquín
- Instituto de Fisiologia Celular. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
| | - Eduardo Cruz-Ramos
- Instituto de Investigaciones Biomedicas. Universidad Nacional Autonoma de Mexico. Mexico City, 04510, Mexico
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41
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Jamous A, Salah Z. WW-Domain Containing Protein Roles in Breast Tumorigenesis. Front Oncol 2018; 8:580. [PMID: 30619734 PMCID: PMC6300493 DOI: 10.3389/fonc.2018.00580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022] Open
Abstract
Protein-protein interactions are key factors in executing protein function. These interactions are mediated through different protein domains or modules. An important domain found in many different types of proteins is WW domain. WW domain-containing proteins were shown to be involved in many human diseases including cancer. Some of these proteins function as either tumor suppressor genes or oncogenes, while others show dual identity. Some of these proteins act on their own and alter the function(s) of specific or multiple proteins implicated in cancer, others interact with their partners to compose WW domain modular pathway. In this review, we discuss the role of WW domain-containing proteins in breast tumorigenesis. We give examples of specific WW domain containing proteins that play roles in breast tumorigenesis and explain the mechanisms through which these proteins lead to breast cancer initiation and progression. We discuss also the possibility of using these proteins as biomarkers or therapeutic targets.
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Affiliation(s)
- Abrar Jamous
- Al Quds-Bard College for Arts and Sciences, Al Quds University, Abu Dis, Palestine
| | - Zaidoun Salah
- Al Quds-Bard College for Arts and Sciences, Al Quds University, Abu Dis, Palestine
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42
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Xia Y, Chang X, Lian S, Zhu W. WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway. J Int Med Res 2018; 46:2898-2912. [PMID: 29888632 PMCID: PMC6124284 DOI: 10.1177/0300060518778905] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been implicated in tumor progression. We aimed to investigate the role of WWP1 in cutaneous squamous cell carcinoma (CSCC). Methods WWP1 gene and protein levels were detected using semi-quantitative reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The effects of WWP1 on cell cycle, apoptosis, cell migration and invasion were examined by flow cytometry, wound healing and Transwell assays, respectively. The antitumor efficacy of WWP1 small interfering RNA was determined in CSCC tumor xenografts in mice. Results WWP1 expression was significantly higher in CSCC tissues and cells than in normal skin and cells, respectively. WWP1 expression was significantly associated with histological grade, invasion depth and lymph node metastasis in patients with CSCC. High expression predicted metastatic potential and an unfavorable prognosis. WWP1 downregulation suppressed tumor growth in vitro and in vivo, reduced cell migration and invasion, arrested the cell cycle in G0/G1 and induced apoptosis in A431 cells. WWP1 depletion also decreased phosphorylated signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2, cyclin D1 and Bcl-2, but did not affect total STAT3. Conclusions WWP1 is a potential target for the diagnosis, prognosis and therapy of patients with CSCC.
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Affiliation(s)
- Yonghua Xia
- Department of Dermatology and Venerology, Xuanwu Hospital, Capital Medical University, Xicheng District, Beijing, P.R. China
| | - Xiao Chang
- Department of Dermatology and Venerology, Xuanwu Hospital, Capital Medical University, Xicheng District, Beijing, P.R. China
| | - Shi Lian
- Department of Dermatology and Venerology, Xuanwu Hospital, Capital Medical University, Xicheng District, Beijing, P.R. China
| | - Wei Zhu
- Department of Dermatology and Venerology, Xuanwu Hospital, Capital Medical University, Xicheng District, Beijing, P.R. China
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43
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Gupta I, Singh K, Varshney NK, Khan S. Delineating Crosstalk Mechanisms of the Ubiquitin Proteasome System That Regulate Apoptosis. Front Cell Dev Biol 2018; 6:11. [PMID: 29479529 PMCID: PMC5811474 DOI: 10.3389/fcell.2018.00011] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/26/2018] [Indexed: 01/10/2023] Open
Abstract
Regulatory functions of the ubiquitin-proteasome system (UPS) are exercised mainly by the ubiquitin ligases and deubiquitinating enzymes. Degradation of apoptotic proteins by UPS is central to the maintenance of cell health, and deregulation of this process is associated with several diseases including tumors, neurodegenerative disorders, diabetes, and inflammation. Therefore, it is the view that interrogating protein turnover in cells can offer a strategy for delineating disease-causing mechanistic perturbations and facilitate identification of drug targets. In this review, we are summarizing an overview to elucidate the updated knowledge on the molecular interplay between the apoptosis and UPS pathways. We have condensed around 100 enzymes of UPS machinery from the literature that ubiquitinates or deubiquitinates the apoptotic proteins and regulates the cell fate. We have also provided a detailed insight into how the UPS proteins are able to fine-tune the intrinsic, extrinsic, and p53-mediated apoptotic pathways to regulate cell survival or cell death. This review provides a comprehensive overview of the potential of UPS players as a drug target for cancer and other human disorders.
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Affiliation(s)
- Ishita Gupta
- Structural Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.,Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Kanika Singh
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Nishant K Varshney
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
| | - Sameena Khan
- Drug Discovery Research Centre, Translational Health Science and Technology Institute, Faridabad, India
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44
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The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia. Leukemia 2017; 32:911-919. [PMID: 29209041 PMCID: PMC5886071 DOI: 10.1038/leu.2017.342] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 10/23/2017] [Accepted: 11/10/2017] [Indexed: 12/20/2022]
Abstract
The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1 cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.
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45
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Wang D, Ma L, Wang B, Liu J, Wei W. E3 ubiquitin ligases in cancer and implications for therapies. Cancer Metastasis Rev 2017; 36:683-702. [DOI: 10.1007/s10555-017-9703-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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46
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Kumari N, Jaynes PW, Saei A, Iyengar PV, Richard JLC, Eichhorn PJA. The roles of ubiquitin modifying enzymes in neoplastic disease. Biochim Biophys Acta Rev Cancer 2017; 1868:456-483. [PMID: 28923280 DOI: 10.1016/j.bbcan.2017.09.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/11/2017] [Accepted: 09/12/2017] [Indexed: 12/22/2022]
Abstract
The initial experiments performed by Rose, Hershko, and Ciechanover describing the identification of a specific degradation signal in short-lived proteins paved the way to the discovery of the ubiquitin mediated regulation of numerous physiological functions required for cellular homeostasis. Since their discovery of ubiquitin and ubiquitin function over 30years ago it has become wholly apparent that ubiquitin and their respective ubiquitin modifying enzymes are key players in tumorigenesis. The human genome encodes approximately 600 putative E3 ligases and 80 deubiquitinating enzymes and in the majority of cases these enzymes exhibit specificity in sustaining either pro-tumorigenic or tumour repressive responses. In this review, we highlight the known oncogenic and tumour suppressive effects of ubiquitin modifying enzymes in cancer relevant pathways with specific focus on PI3K, MAPK, TGFβ, WNT, and YAP pathways. Moreover, we discuss the capacity of targeting DUBs as a novel anticancer therapeutic strategy.
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Affiliation(s)
- Nishi Kumari
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Patrick William Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore
| | - Azad Saei
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore; Genome Institute of Singapore, A*STAR, Singapore
| | | | | | - Pieter Johan Adam Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
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Guo J, Gong G, Zhang B. Screening and identification of potential biomarkers in triple-negative breast cancer by integrated analysis. Oncol Rep 2017; 38:2219-2228. [PMID: 28849078 DOI: 10.3892/or.2017.5911] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 06/29/2017] [Indexed: 11/06/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has attracted great attention due to its unique biology, poor prognosis, and aggressiveness. TNBC patients are more likely to suffer from metastasis. We screened and identified the TNBC-specific genes as potential biomarkers. A total of 167 breast cancer samples (45 TNBC and 122 non-TNBC) were used in the integrated analysis. Gene expression microarrays were used to screen the differentially expressed genes. We identified 65 core DEGs. According to the GO and KEGG analysis, the gene function enrichment in TNBC was revealed, such as basal cell carcinoma, prostate cancer, oocyte meiosis and choline metabolism in cancer pathways. Moreover, the PPI network reconstruction would benefit the screening of hubs. A RFS analysis of TNBC-specific genes was also conducted. RT-PCR was used to validate the expression pattern of hubs in TNBC. Finally, nine genes were identified and all of them were novel, specific and higher dysregulation expressed genes in TNBC. Such that, these genes will serve as potential biomarkers in TNBC and benefit further research in TNBC.
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Affiliation(s)
- Jilong Guo
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia 028000, P.R. China
| | - Guohua Gong
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia 028000, P.R. China
| | - Bin Zhang
- Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia 028000, P.R. China
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Li Q, Li Z, Wei S, Wang W, Chen Z, Zhang L, Chen L, Li B, Sun G, Xu J, Li Q, Wang L, Xu Z, Xia Y, Zhang D, Xu H, Xu Z. Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:59. [PMID: 28431583 PMCID: PMC5401563 DOI: 10.1186/s13046-017-0532-2] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 04/17/2017] [Indexed: 01/08/2023]
Abstract
BACKGROUND MicroRNAs are endogenously expressed, small non-coding RNAs that modulate gene expression by targeting specific mRNAs, resulting in translational repression or mRNA degradation. Although miR-584-5p has been reported to play a vital role in various malignancies, its role and the molecular mechanisms underlying the effects of miR-584-5p in gastric cancer (GC) remain to be clarified. In this study, we investigated the role of miR-584-5p in GC. METHODS The expression of miR-584-5p and its specific target gene were determined in human GC specimens and cell lines by microRNA real-time polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR) and Western blot. The effects of miR-584-5p depletion or ectopic expression on GC proliferation were evaluated in vitro using CCK-8 proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were investigated using a mouse tumorigenicity model. Cell apoptosis was evaluated by in vitro flow cytometric analysis, cell viability assays and in vivo TUNEL assays. Luciferase reporter assays were employed to identify interactions between miR-584-5p and its specific target gene. RESULTS A series of in vitro and in vivo gain- and loss-of-function assays revealed that miR-584-5p inhibited GC cell proliferation, while apoptosis was induced. Luciferase reporter assays and Western blot analysis revealed WWP1 to be a direct target of miR-584-5p. The effects of miR-584-5p-mimic were rescued by WWP1 overexpression. In contrast, the effects of the miR-584-5p-inhibitor were impaired by WWP1-shRNA. Furthermore, miR-584-5p expression levels correlated negatively with WWP1 protein expression in GC tissues and GC cell lines. A series of investigations indicated that miR-584-5p promoted senescence and activated the TGFβ signaling pathway by downregulation of WWP1. CONCLUSION Taken together, these results suggest that downregulation of miR-584-5p contributes to tumor progression by downregulation of WWP1, thus, highlighting the potential of miR-584-5p as a therapeutic target for human GC.
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Affiliation(s)
- Qing Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Zheng Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Song Wei
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Weizhi Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Zheng Chen
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lei Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Liang Chen
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Bowen Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Guangli Sun
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Jianghao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Qiang Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Lu Wang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Zhipeng Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Yiwen Xia
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Diancai Zhang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Hao Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China
| | - Zekuan Xu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou road, Nanjing, Jiangsu province, China.
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Gallo LH, Ko J, Donoghue DJ. The importance of regulatory ubiquitination in cancer and metastasis. Cell Cycle 2017; 16:634-648. [PMID: 28166483 PMCID: PMC5397262 DOI: 10.1080/15384101.2017.1288326] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/20/2017] [Accepted: 01/24/2017] [Indexed: 12/26/2022] Open
Abstract
Ubiquitination serves as a degradation mechanism of proteins, but is involved in additional cellular processes such as activation of NFκB inflammatory response and DNA damage repair. We highlight the E2 ubiquitin conjugating enzymes, E3 ubiquitin ligases and Deubiquitinases that support the metastasis of a plethora of cancers. E3 ubiquitin ligases also modulate pluripotent cancer stem cells attributed to chemotherapy resistance. We further describe mutations in E3 ubiquitin ligases that support tumor proliferation and adaptation to hypoxia. Thus, this review describes how tumors exploit members of the vast ubiquitin signaling pathways to support aberrant oncogenic signaling for survival and metastasis.
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Affiliation(s)
- L. H. Gallo
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - J. Ko
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - D. J. Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
- Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA
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Ma W, Zhao P, Zang L, Zhang K, Liao H, Hu Z. Tumour suppressive function of HUWE1 in thyroid cancer. J Biosci 2017; 41:395-405. [PMID: 27581931 DOI: 10.1007/s12038-016-9623-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
HUWE1 (the HECT, UBA, and WWE domain-containing protein 1) is an ubiquitin E3 ligase which plays an important role in coordinating diverse cellular processes. It has been found to be dysregulated in various cancer type and its functions in tumorigenesis remain controversial. The potential tumour suppressive role of HUWE1 in thyroid cancer development was investigated by knocking down HUWE1 in three authentic thyroid cancer cell lines, WRO, FTC133 and BCPAP, followed by various functional assays, including cell proliferation, scratch wound healing and invasion assays. Xenograft experiment was performed to examine in vivo tumour suppressive properties of HUWE1. Small-interfering RNA mediated knockdown of HUWE1 promoted cell proliferation, cell migration and invasion in thyroid cancer cells. Overexpression of HUWE1 conferred partial sensitivity to chemo drugs interfering with DNA replication in these cells. Moreover, HUWE1 was found to be down-regulated in human thyroid cancer tissues compared with matched normal thyroid tissues. In addition, overexpression of HUWE1 significantly inhibited tumour growth in vivo using xenograft mouse models. Mechanistic investigation revealed that HUWE1 can regulate p53 protein level through its stabilization. HUWE1 functions as a tumour suppressor in thyroid cancer progression, which may represent a novel therapeutic target for prevention or intervention of thyroid cancer.
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Affiliation(s)
- Weiyuan Ma
- The Second Hospital of Hebei Medical University, Shijiazhuang 050000 Hebei Province, China
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