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1
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Li C, Wang K, Fang J, Qin L, Ling Q, Yu Y. TRIM25 activates Wnt/β-catenin signalling by destabilising MAT2A mRNA to drive thoracic aortic aneurysm development. Hum Mol Genet 2024; 33:1890-1899. [PMID: 39216871 DOI: 10.1093/hmg/ddae122] [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: 04/01/2024] [Revised: 07/09/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
This study explored the roles of methionine adenosyltransferase 2A (MAT2A) and tripartite motif containing 25 (TRIM25) in the progression of thoracic aortic aneurysm (TAA). The TAA model was established based on the β-aminopropionitrile method. The effects of MAT2A on thoracic aortic lesions and molecular levels were analyzed by several pathological staining assays (hematoxylin-eosin, Verhoeff-Van Gieson, TUNEL) and molecular biology experiments (qRT-PCR, Western blot). Angiotensin II (Ang-II) was used to induce injury in vascular smooth muscle cells (VSMCs) in vitro. The effects of MAT2A, shMAT2A, shTRIM25 and/or Wnt inhibitor (IWR-1) on the viability, apoptosis and protein expressions of VSMCs were examined by CCK-8, Annexin V-FITC/PI and Western blot assays. In TAA mice, overexpression of MAT2A alleviated thoracic aortic injury, inhibited the aberrant expressions of aortic contractile proteins and dedifferentiation markers, and blocked the activation of Wnt/β-catenin pathway. In Ang-II-induced VSMCs, up-regulation of MAT2A increased cellular activity and repressed the expression of β-catenin protein. TRIM25 knockdown promoted activity of VSMCs, inhibited apoptosis, and blocked the Wnt/β-catenin pathway activation by binding to MAT2A. IWR-1 partially counteracted the regulatory effects of shMAT2A. Collectively, TRIM25 destabilises the mRNA of MAT2A to activate Wnt/β-catenin signaling and ultimately exacerbate TAA injury.
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MESH Headings
- Animals
- Aortic Aneurysm, Thoracic/genetics
- Aortic Aneurysm, Thoracic/metabolism
- Aortic Aneurysm, Thoracic/pathology
- Mice
- Wnt Signaling Pathway/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Methionine Adenosyltransferase/genetics
- Methionine Adenosyltransferase/metabolism
- Myocytes, Smooth Muscle/metabolism
- Apoptosis/genetics
- beta Catenin/metabolism
- beta Catenin/genetics
- Humans
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Tripartite Motif Proteins/genetics
- Tripartite Motif Proteins/metabolism
- Disease Models, Animal
- Male
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Angiotensin II/pharmacology
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Affiliation(s)
- Chaojie Li
- Department of Cardiothoracic Surgery, People's Hospital of Xiangzhou District, No. 178 Lanpu Road, Xiangzhou District, Zhuhai, Guangdong, 519000, China
| | - Kan Wang
- Department of Cardiothoracic Surgery, the Second Clinical College, Guangzhou University of Chinese Medicine, No. 111, Dade Road, Yuexiu District, Guangzhou, Guangdong, 510120, China
- Applicants for Equivalent PhD, Guangzhou University of Chinese Medicine, No. 111, Dade Road, Yuexiu District, Guangzhou, Guangdong, 510120, China
| | - Jian Fang
- Department of Anesthesiology, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, No. 208 Yuehua Road, Zhuhai, Guangdong, 519000, China
| | - Lin Qin
- Department of Ophthalmology, the Second Clinical College, Guangzhou University of Chinese Medicine, No. 111, Dade Road, Yuexiu District, Guangzhou, Guangdong, 510120, China
| | - Qiong Ling
- Department of Anesthesiology, the Second Clinical College, Guangzhou University of Chinese Medicine, No. 111, Dade Road, Yuexiu District, Guangzhou, Guangdong, 510120, China
| | - Yu Yu
- Department of Health Examination, Zhuhai Women and Children's Hospital, No. 543 Ningxi Road, Zhuhai City, Guangdong, 519000, China
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2
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Chiang DC, Yap BK. TRIM25, TRIM28 and TRIM59 and Their Protein Partners in Cancer Signaling Crosstalk: Potential Novel Therapeutic Targets for Cancer. Curr Issues Mol Biol 2024; 46:10745-10761. [PMID: 39451518 PMCID: PMC11506413 DOI: 10.3390/cimb46100638] [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: 08/15/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Aberrant expression of TRIM proteins has been correlated with poor prognosis and metastasis in many cancers, with many TRIM proteins acting as key oncogenic factors. TRIM proteins are actively involved in many cancer signaling pathways, such as p53, Akt, NF-κB, MAPK, TGFβ, JAK/STAT, AMPK and Wnt/β-catenin. Therefore, this review attempts to summarize how three of the most studied TRIMs in recent years (i.e., TRIM25, TRIM28 and TRIM59) are involved directly and indirectly in the crosstalk between the signaling pathways. A brief overview of the key signaling pathways involved and their general cross talking is discussed. In addition, the direct interacting protein partners of these TRIM proteins are also highlighted in this review to give a picture of the potential protein-protein interaction that can be targeted for future discovery and for the development of novel therapeutics against cancer. This includes some examples of protein partners which have been proposed to be master switches to various cancer signaling pathways.
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Affiliation(s)
| | - Beow Keat Yap
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang 11800, Malaysia
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3
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Rahimi-Tesiye M, Zaersabet M, Salehiyeh S, Jafari SZ. The role of TRIM25 in the occurrence and development of cancers and inflammatory diseases. Biochim Biophys Acta Rev Cancer 2023; 1878:188954. [PMID: 37437700 DOI: 10.1016/j.bbcan.2023.188954] [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: 03/30/2023] [Revised: 07/01/2023] [Accepted: 07/08/2023] [Indexed: 07/14/2023]
Abstract
The tripartite motif (TRIM) family proteins are a group of proteins involved in different signaling pathways. The changes in the expression regulation, function, and signaling of this protein family are associated with the occurrence and progression of a wide range of disorders. Given the importance of these proteins in pathogenesis, they can be considered as potential therapeutic targets for many diseases. TRIM25, as an E3-ubiquitin ligase, is involved in the development of various diseases and cellular mechanisms, including antiviral innate immunity and cell proliferation. The clinical studies conducted on restricting the function of this protein have reached promising results that can be further evaluated in the future. Here, we review the regulation of TRIM25 and its function in different diseases and signaling pathways, especially the retinoic acid-inducible gene-I (RIG-I) signaling which prompts many kinds of cancers and inflammatory disorders.
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Affiliation(s)
- Maryam Rahimi-Tesiye
- Faculty of Life Science and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mona Zaersabet
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
| | - Sajad Salehiyeh
- Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyedeh Zahra Jafari
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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4
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Yang C, Ou Y, Zhou Q, Liang Y, Li W, Chen Y, Chen W, Wu S, Chen Y, Dai X, Chen X, Chen T, Jin S, Liu Y, Zhang L, Liu S, Hu Y, Zou L, Mao S, Jiang H. Methionine orchestrates the metabolism vulnerability in cisplatin resistant bladder cancer microenvironment. Cell Death Dis 2023; 14:525. [PMID: 37582769 PMCID: PMC10427658 DOI: 10.1038/s41419-023-06050-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/19/2023] [Accepted: 08/07/2023] [Indexed: 08/17/2023]
Abstract
Metabolism vulnerability of cisplatin resistance in BCa cells remains to be discovered, which we applied integrated multi-omics analysis to elucidate the metabolism related regulation mechanism in bladder cancer (BCa) microenvironment. Integrated multi-omics analysis of metabolomics and proteomics revealed that MAT2A regulated methionine metabolism contributes to cisplatin resistance in BCa cells. We further validated MAT2A and cancer stem cell markers were up-regulated and circARHGAP10 was down-regulated through the regulation of MAT2A protein stability in cisplatin resistant BCa cells. circARHGAP10 formed a complex with MAT2A and TRIM25 to accelerate the degradation of MAT2A through ubiquitin-proteasome pathway. Knockdown of MAT2A through overexpression of circARHGAP10 and restriction of methionine up-take was sufficient to overcome cisplatin resistance in vivo in immuno-deficiency model but not in immuno-competent model. Tumor-infiltrating CD8+ T cells characterized an exhausted phenotype in tumors with low methionine. High expression of SLC7A6 in BCa negatively correlated with expression of CD8. Synergistic inhibition of MAT2A and SLC7A6 could overcome cisplatin resistance in immuno-competent model in vivo. Cisplatin resistant BCa cells rely on methionine for survival and stem cell renewal. circARHGAP10/TRIM25/MAT2A regulation pathway plays an important role in cisplatin resistant BCa cells while circARHGAP10 and SLC7A6 should be evaluated as one of the therapeutic target of cisplatin resistant BCa.
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Affiliation(s)
- Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxi Ou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Quan Zhou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yingchun Liang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Weijian Li
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yiling Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Wensun Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Siqi Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yifan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Xiyu Dai
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Xinan Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Tian Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Shengming Jin
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yufei Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Limin Zhang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Shenghua Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Yun Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China
| | - Lujia Zou
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
| | - Shanhua Mao
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
- Intistute of Urology, Huashan hospital, Fudan University, Shanghai, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
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5
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Zeng L, Zhu Y, Moreno CS, Wan Y. New insights into KLFs and SOXs in cancer pathogenesis, stemness, and therapy. Semin Cancer Biol 2023; 90:29-44. [PMID: 36806560 PMCID: PMC10023514 DOI: 10.1016/j.semcancer.2023.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 09/04/2022] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
Despite the development of cancer therapies, the success of most treatments has been impeded by drug resistance. The crucial role of tumor cell plasticity has emerged recently in cancer progression, cancer stemness and eventually drug resistance. Cell plasticity drives tumor cells to reversibly convert their cell identity, analogous to differentiation and dedifferentiation, to adapt to drug treatment. This phenotypical switch is driven by alteration of the transcriptome. Several pluripotent factors from the KLF and SOX families are closely associated with cancer pathogenesis and have been revealed to regulate tumor cell plasticity. In this review, we particularly summarize recent studies about KLF4, KLF5 and SOX factors in cancer development and evolution, focusing on their roles in cancer initiation, invasion, tumor hierarchy and heterogeneity, and lineage plasticity. In addition, we discuss the various regulation of these transcription factors and related cutting-edge drug development approaches that could be used to drug "undruggable" transcription factors, such as PROTAC and PPI targeting, for targeted cancer therapy. Advanced knowledge could pave the way for the development of novel drugs that target transcriptional regulation and could improve the outcome of cancer therapy.
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Affiliation(s)
- Lidan Zeng
- Department of Pharmacology and Chemical Biology, Department of Hematology and oncology, Winship Cancer Institute, Emory University School of Medicine, USA
| | - Yueming Zhu
- Department of Pharmacology and Chemical Biology, Department of Hematology and oncology, Winship Cancer Institute, Emory University School of Medicine, USA
| | - Carlos S Moreno
- Department of Pathology and Laboratory Medicine, Department of Biomedical Informatics, Winship Cancer Institute, Emory University School of Medicine, USA.
| | - Yong Wan
- Department of Pharmacology and Chemical Biology, Department of Hematology and oncology, Winship Cancer Institute, Emory University School of Medicine, USA.
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6
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Efp/TRIM25 and Its Related Protein, TRIM47, in Hormone-Dependent Cancers. Cells 2022; 11:cells11152464. [PMID: 35954308 PMCID: PMC9368238 DOI: 10.3390/cells11152464] [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: 06/30/2022] [Revised: 08/03/2022] [Accepted: 08/06/2022] [Indexed: 12/24/2022] Open
Abstract
Increasing attention has been paid to the biological roles of tripartite motif-containing (TRIM) family proteins, which typically function as E3 ubiquitin ligases. Estrogen-responsive finger protein (Efp), a member of the TRIM family proteins, also known as TRIM25, was originally identified as a protein induced by estrogen and plays critical roles in promoting endocrine-related cancers, including breast cancer, endometrial cancer, and prostate cancer. The pathophysiological importance of Efp made us interested in the roles of other TRIM family proteins that share a similar structure with Efp. Based on a phylogenetic analysis of the C-terminal region of TRIM family proteins, we focused on TRIM47 as a protein belonging to the same branch as Efp. TRIM47 is a poor prognostic factor in both breast cancer and prostate cancer. Atypical lysine-27-like poly-ubiquitination was involved in the underlying mechanism causing endocrine resistance in breast cancer. We also discuss the functions of Efp and TRIM47 in other types of cancers and innate immunity by introducing substrates the are modified by poly-ubiquitination.
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7
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Palioura D, Lazou A, Drosatos K. Krüppel-like factor (KLF)5: An emerging foe of cardiovascular health. J Mol Cell Cardiol 2022; 163:56-66. [PMID: 34653523 PMCID: PMC8816822 DOI: 10.1016/j.yjmcc.2021.10.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/22/2021] [Accepted: 10/07/2021] [Indexed: 02/03/2023]
Abstract
Krüppel-like factors (KLFs) are DNA-binding transcriptional factors, which regulate various pathways that pertain to development, metabolism and other cellular mechanisms. KLF5 was first cloned in 1993 and by 1999, it was reported as the intestinal-enriched KLF. Beyond findings that have associated KLF5 with normal development and cancer, it has been associated with various types of cardiovascular (CV) complications and regulation of metabolic pathways in the liver, heart, adipose tissue and skeletal muscle. Specifically, increased KLF5 expression has been linked with cardiomyopathy in diabetes, end-stage heart failure, and as well as in vascular atherosclerotic lesions. In this review article, we summarize research findings about transcriptional, post-transcriptional and post-translational regulation of KLF5, as well as the role of KLF5 in the biology of cells and organs that affect cardiovascular health either directly or indirectly. Finally, we propose KLF5 inhibition as an emerging approach for cardiovascular therapeutics.
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Affiliation(s)
- Dimitra Palioura
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;,School of Biology, Aristotle University of Thessaloniki, GR, Greece
| | - Antigone Lazou
- School of Biology, Aristotle University of Thessaloniki, GR, Greece
| | - Konstantinos Drosatos
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
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8
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Tecalco-Cruz AC, Abraham-Juárez MJ, Solleiro-Villavicencio H, Ramírez-Jarquín JO. TRIM25: A central factor in breast cancer. World J Clin Oncol 2021; 12:646-655. [PMID: 34513598 PMCID: PMC8394156 DOI: 10.5306/wjco.v12.i8.646] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/07/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
TRIM25 is emerging as a central factor in breast cancer due to its regulation and function. In particular, it has been shown that: (1) Estrogens modulate TRIM25 gene expression; (2) TRIM25 has activity as an E3-ligase enzyme for ubiquitin; and (3) TRIM25 is also an E3 ligase for interferon-stimulated gene 15 protein in the ISGylation system. Consequently, the proteome of mammary tissue is affected by TRIM25-associated pathways, involved in tumor development and metastasis. Here, we discuss the findings on the mechanisms involved in regulating TRIM25 expression and its functional relevance in breast cancer progression. These studies suggest that TRIM25 may be a biomarker and a therapeutic target for breast cancer.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México (UACM), Mexico 03100, Mexico
| | - María Jazmin Abraham-Juárez
- Laboratorio Nacional de Genómica para la Biodiversidad (LANGEBIO), Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Irapuato 36821, Mexico
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Wei W, Chen W, He N. HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation. J Transl Med 2021; 19:258. [PMID: 34118928 PMCID: PMC8199843 DOI: 10.1186/s12967-021-02812-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/01/2021] [Indexed: 12/13/2022] Open
Abstract
Background Asthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. We conducted this study aiming at exploring the effect of Histone deacetylase 4 (HDAC4)-mediated Kruppel-like factor 5 (KLF5)/Slug/CXC chemokine ligand-12 (CXCL12) axis on the development of asthma in regulation of airway inflammation and remodeling. Methods An asthmatic rat model was induced by ovalbumin (OVA) irrigation, and determined HDAC4, KLF5, Slug, and CXCL12 expression in the lung tissues by RT-qPCR and Western blot assay. OVA was also used to induce a cell model of asthma in human BEAS-2B and HBE135-E6E7bronchial epithelial cells. The airway hyperresponsiveness (AHR), and expression of inflammatory cytokines in model mice were examined using methacholine challenge test and ELISA. The biological behaviors were measured in asthma model bronchial smooth muscle cells (BSMCs) following loss- and gain- function approaches. The interactions between HDAC4, KLF5, Slug, and CXCL12 were also detected by IP assay, dual luciferase gene reporter assay, and ChIP. Results HDAC4 was upregulated in lung tissues of OVA-induced asthmatic mice, and inhibition of HDAC4 alleviated the airway inflammation and remodeling. HDAC4 increased KLF5 transcriptional activity through deacetylation; deacetylated KLF5 bound to the promoter of Slug and transcriptionally upregulated Slug expression, which in turn increased the expression of CXCL12 to promote the inflammation in bronchial epithelial cells and thus induce the proliferation and migration of BSMCs. Conclusion Collectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby causing airway remodeling and facilitating progression of asthma. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02812-7.
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Affiliation(s)
- Wendi Wei
- Department of Hepatology, Taian Hospital of Traditional Chinese Medicine, Taian, 271000, People's Republic of China
| | - Weida Chen
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, People's Republic of China
| | - Naifeng He
- School of Health, Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong, People's Republic of China.
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10
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Luo Y, Chen C. The roles and regulation of the KLF5 transcription factor in cancers. Cancer Sci 2021; 112:2097-2117. [PMID: 33811715 PMCID: PMC8177779 DOI: 10.1111/cas.14910] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/11/2022] Open
Abstract
Krüppel‐like factor 5 (KLF5) is a member of the KLF family. Recent studies have suggested that KLF5 regulates the expression of a large number of new target genes and participates in diverse cellular functions, such as stemness, proliferation, apoptosis, autophagy, and migration. In response to multiple signaling pathways, various transcriptional modulation and posttranslational modifications affect the expression level and activity of KLF5. Several transgenic mouse models have revealed the physiological and pathological functions of KLF5 in different cancers. Studies of KLF5 will provide prognostic biomarkers, therapeutic targets, and potential drugs for cancers.
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Affiliation(s)
- Yao Luo
- Medical Faculty of Kunming University of Science and Technology, Kunming, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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11
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Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, Ma X, Cheng Z, Yu C, Wang S, Zuo Q, Zhou Y, Wang J, Yang C, Lv Y, Jiang L, Qin W. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun 2021; 12:295. [PMID: 33436560 PMCID: PMC7804955 DOI: 10.1038/s41467-020-20527-z] [Citation(s) in RCA: 349] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023] Open
Abstract
Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.
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MESH Headings
- Animals
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/pathology
- Cell Proliferation
- DEAD Box Protein 58/metabolism
- Disease Progression
- Down-Regulation/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/immunology
- Lung Neoplasms/pathology
- Mice, Inbred BALB C
- Mice, Nude
- Models, Biological
- Neoplasm Metastasis
- Proteasome Endopeptidase Complex/metabolism
- Protein Binding
- Protein Stability
- Proteolysis
- RNA, Circular/genetics
- RNA, Circular/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA-Binding Proteins/metabolism
- Receptors, Immunologic
- Transcription Factors/metabolism
- Tripartite Motif Proteins/metabolism
- Ubiquitin/metabolism
- Ubiquitin-Protein Ligases/metabolism
- Ubiquitination
- Mice
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Affiliation(s)
- Botai Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Biomedical Engineering, 200032, Shanghai, China
| | - Lili Zhu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Biomedical Engineering, 200032, Shanghai, China
| | - Chunlai Lu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Cun Wang
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Hui Wang
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Haojie Jin
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Xuhui Ma
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Zhuoan Cheng
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Biomedical Engineering, 200032, Shanghai, China
| | - Chengtao Yu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Biomedical Engineering, 200032, Shanghai, China
| | - Siying Wang
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Qiaozhu Zuo
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Yangyang Zhou
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Jun Wang
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Chen Yang
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Yuanyuan Lv
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Liyan Jiang
- Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 200030, Shanghai, China.
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Biomedical Engineering, 200032, Shanghai, China.
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China.
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12
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Khan KA, Marineau A, Doyon P, Acevedo M, Durette É, Gingras AC, Servant MJ. TRK-Fused Gene (TFG), a protein involved in protein secretion pathways, is an essential component of the antiviral innate immune response. PLoS Pathog 2021; 17:e1009111. [PMID: 33411856 PMCID: PMC7790228 DOI: 10.1371/journal.ppat.1009111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 10/30/2020] [Indexed: 12/15/2022] Open
Abstract
Antiviral innate immune response to RNA virus infection is supported by Pattern-Recognition Receptors (PRR) including RIG-I-Like Receptors (RLR), which lead to type I interferons (IFNs) and IFN-stimulated genes (ISG) production. Upon sensing of viral RNA, the E3 ubiquitin ligase TNF Receptor-Associated Factor-3 (TRAF3) is recruited along with its substrate TANK-Binding Kinase (TBK1), to MAVS-containing subcellular compartments, including mitochondria, peroxisomes, and the mitochondria-associated endoplasmic reticulum membrane (MAM). However, the regulation of such events remains largely unresolved. Here, we identify TRK-Fused Gene (TFG), a protein involved in the transport of newly synthesized proteins to the endomembrane system via the Coat Protein complex II (COPII) transport vesicles, as a new TRAF3-interacting protein allowing the efficient recruitment of TRAF3 to MAVS and TBK1 following Sendai virus (SeV) infection. Using siRNA and shRNA approaches, we show that TFG is required for virus-induced TBK1 activation resulting in C-terminal IRF3 phosphorylation and dimerization. We further show that the ability of the TRAF3-TFG complex to engage mTOR following SeV infection allows TBK1 to phosphorylate mTOR on serine 2159, a post-translational modification shown to promote mTORC1 signaling. We demonstrate that the activation of mTORC1 signaling during SeV infection plays a positive role in the expression of Viperin, IRF7 and IFN-induced proteins with tetratricopeptide repeats (IFITs) proteins, and that depleting TFG resulted in a compromised antiviral state. Our study, therefore, identifies TFG as an essential component of the RLR-dependent type I IFN antiviral response. Antiviral innate immune response is the first line of defence against the invading viruses through type I interferon (IFN) signaling. However, viruses have devised ways to target signaling molecules for aberrant IFN response and worsen the disease outcome. As such, deciphering the roles of new regulators of innate immunity could transform the antiviral treatment paradigm by introducing novel panviral therapeutics designed to reinforce antiviral host responses. This could be of great use in fighting recent outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome MERS-CoV, and the more recent SARS-CoV-2 causing the COVID-19 pandemic. However, aberrant activation of such pathways can lead to detrimental consequences, including autoimmune diseases. Regulation of type I IFN responses is thus of paramount importance. To prevent an uncontrolled response, signaling events happen in discrete subcellular compartments, therefore, distinguishing sites involved in recognition of pathogens and those permitting downstream signaling. Here, we show TFG as a new regulator of type I IFN response allowing the efficient organization of signaling molecules. TFG, thus, further substantiates the importance of the protein trafficking machinery in the regulation of optimal antiviral responses. Our findings have implications for both antiviral immunity and autoimmune diseases.
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Affiliation(s)
| | | | - Priscilla Doyon
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
| | - Mariana Acevedo
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
| | - Étienne Durette
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
| | - Anne-Claude Gingras
- Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Marc J. Servant
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
- * E-mail:
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13
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Fu J, Zheng H, Xue Y, Jin R, Yang G, Chen Z, Yuan G. WWP2 Promotes Odontoblastic Differentiation by Monoubiquitinating KLF5. J Dent Res 2020; 100:432-439. [PMID: 33164644 DOI: 10.1177/0022034520970866] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
WW domain-containing E3 Ub-protein ligase 2 (WWP2) belongs to the homologous to E6AP C-terminus (HECT) E3 ligase family. It has been explored to regulate osteogenic differentiation, chondrogenesis, and palatogenesis. Odontoblasts are terminally differentiated mesenchymal cells, which contribute to dentin formation in tooth development. However, it remained unknown whether WWP2 participated in odontoblast differentiation. In this study, WWP2 was found to be expressed in mouse dental papilla cells (mDPCs), odontoblasts, and odontoblastic-induced mDPCs by immunohistochemistry and Western blotting. Besides, WWP2 expression was decreased in the cytoplasm but increased in the nuclei of differentiation-induced mDPCs. When Wwp2 was knocked down, the elevated expression of odontoblast marker genes (Dmp1 and Dspp) in mDPCs induced by differentiation medium was suppressed. Meanwhile, a decrease of alkaline phosphatase (ALP) activity was observed by ALP staining, and reduced formation of mineralized matrix nodules was demonstrated by Alizarin Red S staining. Overexpression of WWP2 presented opposite results to knockdown experiments, suggesting that WWP2 promoted odontoblastic differentiation of mDPCs. Further investigation found that WWP2 was coexpressed and interacted with KLF5 in the nuclei, leading to ubiquitination of KLF5. The PPPSY (PY2) motif of KLF5 was essential for its physical binding with WWP2. Also, cysteine 838 (Cys838) of WWP2 was the active site for ubiquitination of KLF5, which did not lead to proteolysis of KLF5. Then, KLF5 was confirmed to be monoubiquitinated and transactivated by WWP2, which promoted the expression of KLF5 downstream genes Dmp1 and Dspp. Deletion of the PY2 motif of KLF5 or mutation of Cys838 of WWP2 reduced the upregulation of Dmp1 and Dspp. Besides, lysine (K) residues K31, K52, K83, and K265 of KLF5 were verified to be crucial to WWP2-mediated KLF5 transactivation. Taken together, WWP2 promoted odontoblastic differentiation by monoubiquitinating KLF5.
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Affiliation(s)
- J Fu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - H Zheng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - Y Xue
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - R Jin
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - G Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - Z Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
| | - G Yuan
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, HuBei, China
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14
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Ma JB, Bai JY, Zhang HB, Jia J, Shi Q, Yang C, Wang X, He D, Guo P. KLF5 inhibits STAT3 activity and tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with HDAC1. Cell Death Dis 2020; 11:466. [PMID: 32546700 PMCID: PMC7297795 DOI: 10.1038/s41419-020-2671-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/04/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023]
Abstract
KLF5 is frequently deleted and downregulated in prostate cancer, and recently it has been reported that KLF5 loss is enriched in the aggressive branches of prostate cancer evolution. However, why KLF5 loss is associated with prostate cancer aggressiveness is still not clear. Herein, we analyzed KLF5 expression in TCGA and GEO database, as well as prostate cancer tissue microarray, and found that KLF5 expression significantly decreased in prostate cancer accompanying with tumor progression; moreover, KLF5 downregulation was associated with shorter survival of patients. Interestingly, we also found that KLF5 expression was obviously lower in prostate cancer metastases than in localized tissues, indicating that KLF5 downregulation is associated with prostate cancer invasion and metastasis. To assess this effect of KLF5, we knocked down KLF5 in prostate cancer cells and found that KLF5 knockdown promoted invasive ability of prostate cancer cells in vitro and in vivo. Moreover, we found that KLF5 downregulation enhanced the expression of IGF1 and STAT3 phosphorylation, while block of IGF1 with antibody decreased the enhancement of STAT3 activity and prostate cancer cell invasive ability by KLF5 knockdown, indicating that KLF5 inhibits prostate cancer invasion through suppressing IGF1/STAT3 pathway. Mechanistically, we found that KLF5 interacted with deacetylase HDAC1 and KLF5 is necessary for the binding of HDAC1 on IGF1 promoter to suppress IGF1 transcription. Taken together, our results indicate that KLF5 could be an important suppressor of prostate cancer invasion and metastasis, because KLF5 could suppress the transcription of IGF1, a tumor cell autocrine cytokine, and its downstream cell signaling to inhibit cell invasive ability, and reveal a novel mechanism for STAT3 activation in prostate cancer. These findings may provide evidence for the precision medicine in prostate cancer.
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Affiliation(s)
- Jian-Bin Ma
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ji-Yu Bai
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hai-Bao Zhang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jing Jia
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Qi Shi
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Chao Yang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xinyang Wang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Key laboratory for Tumor Precision Medicine of Shaanxi Province, Xi'an, Shaanxi, China.,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China
| | - Dalin He
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. .,Key laboratory for Tumor Precision Medicine of Shaanxi Province, Xi'an, Shaanxi, China. .,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
| | - Peng Guo
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. .,Key laboratory for Tumor Precision Medicine of Shaanxi Province, Xi'an, Shaanxi, China. .,Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
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15
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Wu Y, Qin J, Li F, Yang C, Li Z, Zhou Z, Zhang H, Li Y, Wang X, Liu R, Tao Q, Chen W, Chen C. USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5. J Biol Chem 2019; 294:17837-17847. [PMID: 31624151 DOI: 10.1074/jbc.ra119.009102] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
The Krüppel-like factor 5 (KLF5) transcription factor is highly expressed in basal type breast cancer and promotes breast cancer cell proliferation, survival, migration, and tumorigenesis. KLF5 protein stability is regulated by ubiquitination. In this study, ubiquitin-specific protease 3 (USP3) was identified as a new KLF5 deubiquitinase by genome-wide siRNA library screening. We demonstrated that USP3 interacts with KLF5 and stabilizes KLF5 via deubiquitination. USP3 knockdown inhibits breast cancer cell proliferation in vitro and tumorigenesis in vivo, which can be partially rescued by ectopic expression of KLF5. Furthermore, we observed a positive correlation between USP3 and KLF5 protein expression levels in human breast cancer samples. These findings suggest that USP3 is a new KLF5 deubiquitinase and that USP3 may represent a potential therapeutic target for breast cancer.
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Affiliation(s)
- Yingying Wu
- 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.,University of the Chinese Academy of Sciences, Beijing 101407, China.,First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Junying Qin
- 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
| | - Fubing Li
- 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
| | - Chuanyu Yang
- 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
| | - Zhen Li
- Department of Breast Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China
| | - Zhongmei Zhou
- 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
| | - Hailin Zhang
- 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
| | - Yunxi Li
- Department of Breast Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China
| | - Xinye Wang
- 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
| | - 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, 650223, China
| | - Qian Tao
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir Y. K. Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong 518172, China
| | - Wenlin Chen
- Department of Breast Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, 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 Institute of Zoology-Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute of Stem Cell and Reproductive Biology, Chinese Academy of Sciences, Beijing, 100101, China
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16
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Yan W, Wu J, Song B, Luo Q, Xu Y. Treatment with a brain-selective prodrug of 17β-estradiol improves cognitive function in Alzheimer's disease mice by regulating klf5-NF-κB pathway. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:879-886. [PMID: 30879099 PMCID: PMC7260153 DOI: 10.1007/s00210-019-01639-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/22/2019] [Indexed: 12/19/2022]
Abstract
10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) which is a brain-selective prodrug of 17β-estradiol has been reported to improve the cognitive function in Alzheimer’s disease (AD) mice model. However, little is known about the potential mechanism for cognitive improvement. In the present study, we used AD mice to investigate the effects and mechanisms of DHED treatment. Female Tg2576 transgenic AD mice were ovariectomized and then treated by implanting Alzet osmotic minipumps containing DHED or vehicle subcutaneously for 8 weeks. Consistent with previous report, DHED treatment ameliorated cognitive function of AD mice with decreasing Aβ levels in the hippocampus. Besides, we also found DHED treatment could reduce oxidative and inflammatory stress and the level of p-tau. The mechanisms underlying the cognitive function improvement may be linked with estrogen receptor (ER)-klf5-NF-κB pathway, demonstrated by decreased expression of klf5 and the secretion of inflammatory cytokines. However, the effects of DHED treatment could be reversed when ERα was inhibited by ICI182780. Taken together, our findings uncovered a new mechanism for DHED to improve the cognitive function of AD mice and may provide a viable therapy to treat AD.
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Affiliation(s)
- Wenhao Yan
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jun Wu
- Department of Neurology, Shenzhen Hospital of Peking University, Shenzhen, 518036, China
| | - Bo Song
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450002, China
| | - Qiang Luo
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450002, China.
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17
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Sato W, Ikeda K, Urano T, Abe Y, Nakasato N, Horie-Inoue K, Takeda S, Inoue S. Efp promotes in vitro and in vivo growth of endometrial cancer cells along with the activation of nuclear factor-κB signaling. PLoS One 2018; 13:e0208351. [PMID: 30586414 PMCID: PMC6306158 DOI: 10.1371/journal.pone.0208351] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/15/2018] [Indexed: 01/05/2023] Open
Abstract
Endometrial cancer is common among postmenopausal women and its incidence is increasing in developed countries. Considering that >80% of endometrial cancers are assumed to be estrogen-related, higher estrogen exposure will be relevant to tumorigenesis. Therefore, the roles of estrogen target genes will be important to understand the pathophysiological mechanisms. We previously revealed that estrogen-responsive RING finger protein Efp contributes to breast cancer progression through the protein degradation of cell cycle checkpoint 14-3-3σ. We and others also proposed that Efp has tumor-promoting activities in estrogen receptor (ER)-negative cancer cells. In addition, Efp plays a role in type I interferon production by activating antiviral signaling, which provokes nuclear factor-κB (NF-κB) signaling. In the present study, we investigate whether Efp plays a critical role in endometrial cancer biology. We show that siRNA-mediated Efp knockdown represses the proliferation and migration of endometrial cancer ER-positive Ishikawa and ER-negative HEC-1A cells. Efp knockdown increases 14-3-3σ protein levels and decreases the rates proliferative stage cells. Efp siRNA significantly inhibits the in vivo tumor growth of endometrial cancer cells in both subcutaneous and orthotopic xenograft models. Intriguingly, Efp knockdown represses NF-κB-dependent transactivation and transcription of target genes, such as IL6ST and IL18, in endometrial cancer cells. Overall, Efp would exert a tumor-promoting role through modulating NF-κB pathway and 14-3-3σ protein degradation in endometrial cancer regardless of its estrogen receptor status. Our results indicate that Efp could be a potential diagnostic and therapeutic target for endometrial cancer.
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Affiliation(s)
- Wataru Sato
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
| | - Tomohiko Urano
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Yayoi Abe
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
- Department of Obstetrics and Gynecology, School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan
| | - Norie Nakasato
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan
| | - Kuniko Horie-Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
| | - Satoru Takeda
- Department of Obstetrics and Gynecology, School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, Saitama, Japan
| | - Satoshi Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan
- Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan
- * E-mail:
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18
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Moulton VR. Sex Hormones in Acquired Immunity and Autoimmune Disease. Front Immunol 2018; 9:2279. [PMID: 30337927 PMCID: PMC6180207 DOI: 10.3389/fimmu.2018.02279] [Citation(s) in RCA: 375] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 09/13/2018] [Indexed: 12/15/2022] Open
Abstract
Women have stronger immune responses to infections and vaccination than men. Paradoxically, the stronger immune response comes at a steep price, which is the high incidence of autoimmune diseases in women. The reasons why women have stronger immunity and higher incidence of autoimmunity are not clear. Besides gender, sex hormones contribute to the development and activity of the immune system, accounting for differences in gender-related immune responses. Both innate and adaptive immune systems bear receptors for sex hormones and respond to hormonal cues. This review focuses on the role of sex hormones particularly estrogen, in the adaptive immune response, in health, and autoimmune disease with an emphasis on systemic lupus erythematosus.
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Affiliation(s)
- Vaishali R Moulton
- Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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19
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Tao R, Zhang B, Li Y, King JL, Tian R, Xia S, Schiavon CR, Dong JT. HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation. Biochem Biophys Res Commun 2018; 500:777-782. [PMID: 29679567 DOI: 10.1016/j.bbrc.2018.04.153] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 04/17/2018] [Indexed: 01/07/2023]
Abstract
Krüppel-like factor 5 (KLF5) is a basic transcription factor that regulates diverse cellular processes during tumor development. Acetylation of KLF5 at lysine 369 (K369) reverses its function from promoting to suppressing cell proliferation and tumor growth. In this study, we examined the regulation of KLF5 by histone deacetylases in the prostate cancer cell line DU 145. While confirming the functions of HDAC1/2 in KLF5 deacetylation and the promotion of cell proliferation, we found that the knockdown of HDAC1/2 upregulated KLF5 protein but not KLF5 mRNA, and the increase in KLF5 protein level by silencing HDAC1/2 was at least in part due to decreased proteasomal degradation. Deacetylase activity was required for HDAC1/2-mediated KLF5 degradation, and mutation of KLF5 to an acetylation-mimicking form prevented its degradation, even though the mutation did not affect the binding of KLF5 with HDAC1/2. Mutation of K369 to arginine, which prevents acetylation, did not affect the binding of KLF5 to HDAC1 or the response of KLF5 to HDAC1/2-promoted degradation. These findings provide a novel mechanistic association between the acetylation status of KLF5 and its protein stability. They also suggest that maintaining KLF5 in a deacetylated form may be an important mechanism by which KLF5 and HDACs promote cell proliferation and tumor growth.
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Affiliation(s)
- Ran Tao
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA; Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Baotong Zhang
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA
| | - Yixiang Li
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA
| | - Jamie L King
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA
| | - Ruoyu Tian
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China
| | - Siyuan Xia
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA
| | - Cara Rae Schiavon
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA
| | - Jin-Tang Dong
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road, Atlanta, GA 30322, USA; Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
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20
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Wang S, Kollipara RK, Humphries CG, Ma SH, Hutchinson R, Li R, Siddiqui J, Tomlins SA, Raj GV, Kittler R. The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. Oncotarget 2018; 7:64921-64931. [PMID: 27626314 PMCID: PMC5323126 DOI: 10.18632/oncotarget.11915] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 09/02/2016] [Indexed: 11/25/2022] Open
Abstract
Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.
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Affiliation(s)
- Shan Wang
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Rahul K Kollipara
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Caroline G Humphries
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Shi-Hong Ma
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Ryan Hutchinson
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Rui Li
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Javed Siddiqui
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Scott A Tomlins
- Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ganesh V Raj
- Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
| | - Ralf Kittler
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.,Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.,Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
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21
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Takayama KI, Suzuki T, Tanaka T, Fujimura T, Takahashi S, Urano T, Ikeda K, Inoue S. TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer. Oncogene 2018; 37:2165-2180. [DOI: 10.1038/s41388-017-0095-x] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 11/13/2017] [Accepted: 12/05/2017] [Indexed: 01/16/2023]
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22
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Fu RJ, He W, Wang XB, Li L, Zhao HB, Liu XY, Pang Z, Chen GQ, Huang L, Zhao KW. DNMT1-maintained hypermethylation of Krüppel-like factor 5 involves in the progression of clear cell renal cell carcinoma. Cell Death Dis 2017; 8:e2952. [PMID: 28749461 PMCID: PMC5550868 DOI: 10.1038/cddis.2017.323] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/27/2017] [Accepted: 06/08/2017] [Indexed: 12/13/2022]
Abstract
Clear cell renal cell carcinoma (ccRCC) is the major subtype of renal cell carcinoma (RCC) that is resistant to conventional radiation and chemotherapy. It is a challenge to explore effective therapeutic targets and drugs for this kind of cancer. Transcription factor Krüppel-like factor 5 (KLF5) exerts diverse functions in various tumor types. By analyzing cohorts of the Cancer Genome Atlas (TCGA) data sets, we find that KLF5 expression is suppressed in ccRCC patients and higher level of KLF5 expression is associated with better prognostic outcome. Our further investigations demonstrate that KLF5 genomic loci are hypermethylated at proximal exon 4 and suppression of DNA methyltransferase 1 (DNMT1) expression by ShRNAs or a methylation inhibitor 5-Aza-CdR can recover KLF5 expression. Meanwhile, there is a negative correlation between expressions of KLF5 and DNMT1 in ccRCC tissues. Ectopic KLF5 expression inhibits ccRCC cell proliferation and migration/invasion in vitro and decreases xenograft growth and metastasis in vivo. Moreover, 5-Aza-CdR, a chemotherapy drug as DNMTs' inhibitor that can induce KLF5 expression, suppresses ccRCC cell growth, while knockdown of KLF5 abolishes 5-Aza-CdR-induced growth inhibition. Collectively, our data demonstrate that KLF5 inhibits ccRCC growth as a tumor suppressor and highlight the potential of 5-Aza-CdR to release KLF5 expression as a therapeutic modality for the treatment of ccRCC.
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Affiliation(s)
- Rong-Jie Fu
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS) &Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Wei He
- Department of Pathology, Ren-Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Bo Wang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Lei Li
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Huan-Bin Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Xiao-Ye Liu
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS) &Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Zhi Pang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Guo-Qiang Chen
- Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS) &Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.,Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Lei Huang
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
| | - Ke-Wen Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China
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23
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The role of Trim25 in development, disease and RNA metabolism. Biochem Soc Trans 2017; 44:1045-50. [PMID: 27528750 DOI: 10.1042/bst20160077] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Indexed: 12/13/2022]
Abstract
Trim25 is a member of the tripartite motif family of E3 ubiquitin ligases. It plays major roles in innate immunity and defence against viral infection, control of cell proliferation and migration of cancer cells. Recent work identified Trim25 as being able to bind to RNA and to regulate Lin28a-mediated uridylation of pre-let-7. Here we review the current knowledge of the role of Trim25 in development, disease and RNA metabolism.
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24
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Ge F, Chen W, Qin J, Zhou Z, Liu R, Liu L, Tan J, Zou T, Li H, Ren G, Chen C. Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5). Oncotarget 2016; 6:21369-78. [PMID: 26079537 PMCID: PMC4673271 DOI: 10.18632/oncotarget.4128] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/02/2015] [Indexed: 11/25/2022] Open
Abstract
The Krüppel-like factor 5 (KLF5) has been suggested to promote breast cell proliferation, survival and tumorigenesis. KLF5 protein degradation is increased by several E3 ubiquitin ligases, including WWP1 and SCFFbw7, through the ubiquitin-proteasome pathway. However, the deubiquitinase (DUB) of KLF5 has not been demonstrated. In this study, we identified ATXN3L as a KLF5 DUB by genome-wide siRNA screening. ATXN3L directly binds to KLF5, decreasing its ubiquitination and thus degradation. Functionally, knockdown of ATXN3L inhibits breast cancer cell proliferation partially through KLF5. These findings reveal a previously unrecognized role of ATXN3L in the regulation of KLF5 stability in breast cancer. ATXN3L might be a therapeutic target for breast cancer.
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Affiliation(s)
- Fei Ge
- 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, Yunnan, China.,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenlin Chen
- Department of Breast Surgery, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Junying Qin
- 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, Yunnan, China
| | - Zhongmei Zhou
- 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, Yunnan, 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, Yunnan, China
| | - Linlin Liu
- Laboratory for Conservation and Utilization of Bioresource, Yunnan University, Kunming, China
| | - Jing Tan
- Department of Breast Surgery, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Tianning Zou
- Department of Breast Surgery, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hongyuan Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 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, Yunnan, China
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25
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Nakajima Y, Osakabe A, Waku T, Suzuki T, Akaogi K, Fujimura T, Homma Y, Inoue S, Yanagisawa J. Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway. Mol Cell Biol 2016; 36:144-56. [PMID: 26483416 PMCID: PMC4702593 DOI: 10.1128/mcb.00625-15] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 07/14/2015] [Accepted: 10/09/2015] [Indexed: 11/20/2022] Open
Abstract
Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.
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Affiliation(s)
- Yuka Nakajima
- Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
| | - Asami Osakabe
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
| | - Tsuyoshi Waku
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
| | - Takashi Suzuki
- Department of Pathology and Histotechnology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kensuke Akaogi
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
| | - Tetsuya Fujimura
- Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yukio Homma
- Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan
| | - Junn Yanagisawa
- Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
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26
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Wang J, Zhu J, Dong M, Yu H, Dai X, Li K. Knockdown of tripartite motif containing 24 by lentivirus suppresses cell growth and induces apoptosis in human colorectal cancer cells. Oncol Res 2015; 22:39-45. [PMID: 25700357 PMCID: PMC7592803 DOI: 10.3727/096504014x14078436005012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer remains one of the most common cancers in men and women, and it accounts for a large proportion of cancer-related deaths worldwide. Tripartite motif (TRIM) proteins are a novel class of “single protein RING finger” E3 ubiquitin ligases, which have been shown to be involved in many cancers. The aim of this study was to investigate the potential role of TRIM24 in human colorectal cancer. By using a lentivirus-mediated RNA interference system, we first explored the effect of TRIM24 knockdown on HCT116 cell proliferation and colony formation. Moreover, flow cytometry analysis was used to examine its effects on cell cycle distribution and apoptosis. Our data showed that knockdown of TRIM24 expression in HCT116 cells significantly decreased cell growth due to the induction of apoptosis. Hence, the present study provides evidence that TRIM24 functions as an oncogene in colorectal carcinogenesis.
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Affiliation(s)
- Jianwei Wang
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Jinhui Zhu
- Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
| | - Mingjun Dong
- Department of Anorectal Surgery, Ningbo Second HospitalNingboChina
| | - Hua Yu
- Department of Anorectal Surgery, Ningbo Second HospitalNingboChina
| | - Xiaoyu Dai
- Department of Anorectal Surgery, Ningbo Second HospitalNingboChina
| | - Keqiang Li
- Clinical Research Center, Ningbo Second Hospital, Key Laboratory of Molecular Biology of CancerNingboChina
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27
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Qin Y, Cui H, Zhang H. Overexpression of TRIM25 in Lung Cancer Regulates Tumor Cell Progression. Technol Cancer Res Treat 2015; 15:707-15. [PMID: 26113559 DOI: 10.1177/1533034615595903] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/28/2015] [Indexed: 12/18/2022] Open
Abstract
Lung cancer is one of the most common causes of cancer-related deaths worldwide. Although great efforts and progressions have been made in the study of the lung cancer in the recent decades, the mechanism of lung cancer formation remains elusive. To establish effective therapeutic methods, new targets implied in lung cancer processes have to be identified. Tripartite motif-containing 25 has been associated with ovarian and breast cancer and is thought to positively promote cell growth by targeting the cell cycle. However, whether tripartite motif-containing 25 has a function in lung cancer development remains unknown. In this study, we found that tripartite motif-containing 25 was overexpressed in human lung cancer tissues. Expression of tripartite motif-containing 25 in lung cancer cells is important for cell proliferation and migration. Knockdown of tripartite motif-containing 25 markedly reduced proliferation of lung cancer cells both in vitro and in vivo and reduced migration of lung cancer cells in vitro Meanwhile, tripartite motif-containing 25 silencing also increased the sensitivity of doxorubicin and significantly increased death and apoptosis of lung cancer cells by doxorubicin were achieved with knockdown of tripartite motif-containing 25. We also observed that tripartite motif-containing 25 formed a complex with p53 and mouse double minute 2 homolog (MDM2) in both human lung cancer tissues and in lung cancer cells and tripartite motif-containing 25 silencing increased the expression of p53. These results provide evidence that tripartite motif-containing 25 contributes to the pathogenesis of lung cancer probably by promoting proliferation and migration of lung cancer cells. Therefore, targeting tripartite motif-containing 25 may provide a potential therapeutic intervention for lung cancer.
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Affiliation(s)
- Ying Qin
- Department of Anatomy and Histology, Shandong Medical College, Jinan, Shandong, People's Republic of China
| | - He Cui
- Department of Physiology, Shandong Medical College, Jinan, Shandong, People's Republic of China
| | - Hua Zhang
- Department of Anatomy and Histology, Shandong Medical College, Jinan, Shandong, People's Republic of China
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28
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Luan Y, Wang P. FBW7-mediated ubiquitination and degradation of KLF5. World J Biol Chem 2014; 5:216-223. [PMID: 24921010 PMCID: PMC4050114 DOI: 10.4331/wjbc.v5.i2.216] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 01/15/2014] [Accepted: 03/18/2014] [Indexed: 02/05/2023] Open
Abstract
Krüppel-like factor (KLF) family proteins are transcription factors that regulate numerous cellular functions, such as cell proliferation, differentiation, and cell death. Posttranslational modification of KLF proteins is important for their transcriptional activities and biological functions. One KLF family member with important roles in cell proliferation and tumorigenesis is KLF5. The function of KLF5 is tightly controlled by post-translational modifications, including SUMOylation, phosphorylation, and ubiquitination. Recent studies from our lab and others’ have demonstrated that the tumor suppressor FBW7 is an essential E3 ubiquitin ligase that targets KLF5 for ubiquitination and degradation. KLF5 contains functional Cdc4 phospho-degrons (CPDs), which are required for its interaction with FBW7. Mutation of CPDs in KLF5 blocks the ubiquitination and degradation of KLF5 by FBW7. The protein kinase Glycogen synthase kinase 3β is involved in the phosphorylation of KLF5 CPDs. In both cancer cell lines and mouse models, it has been shown that FBW7 regulates the expression of KLF5 target genes through the modulation of KLF5 stability. In this review, we summarize the current progress on delineating FBW7-mediated KLF5 ubiquitination and degradation.
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29
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Diakiw SM, D'Andrea RJ, Brown AL. The double life of KLF5: Opposing roles in regulation of gene-expression, cellular function, and transformation. IUBMB Life 2013; 65:999-1011. [DOI: 10.1002/iub.1233] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 11/13/2013] [Indexed: 01/13/2023]
Affiliation(s)
- Sonya M. Diakiw
- Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre; University of New South Wales; Australia
- Department of Haematology; SA Pathology; Adelaide Australia
| | - Richard J. D'Andrea
- Department of Haematology; SA Pathology; Adelaide Australia
- School of Pharmacy and Medical Sciences; University of South Australia; Australia
- Centre for Cancer Biology, SA Pathology; Adelaide Australia
- School of Medicine; University of Adelaide; Adelaide Australia
| | - Anna L. Brown
- Department of Haematology; SA Pathology; Adelaide Australia
- School of Pharmacy and Medical Sciences; University of South Australia; Australia
- Centre for Cancer Biology, SA Pathology; Adelaide Australia
- School of Molecular and Biomedical Sciences; University of Adelaide; Adelaide Australia
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30
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Abstract
Krüppel-like factors (KLFs) are a family of DNA-binding transcriptional regulators with diverse and essential functions in a multitude of cellular processes, including proliferation, differentiation, migration, inflammation and pluripotency. In this Review, we discuss the roles and regulation of the 17 known KLFs in various cancer-relevant processes. Importantly, the functions of KLFs are context dependent, with some KLFs having different roles in normal cells and cancer, during cancer development and progression and in different cancer types. We also identify key questions for the field that are likely to lead to important new translational research and discoveries in cancer biology.
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Affiliation(s)
- Marie-Pier Tetreault
- Department of Medicine, Gastroenterology Division, University of Pennsylvania Perelman School of Medicine, 913 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia PA 19104-6144, USA
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31
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Identification and characterization of multiple TRIM proteins that inhibit hepatitis B virus transcription. PLoS One 2013; 8:e70001. [PMID: 23936368 PMCID: PMC3731306 DOI: 10.1371/journal.pone.0070001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 06/18/2013] [Indexed: 01/05/2023] Open
Abstract
Tripartite motif (TRIM) proteins constitute a family of over 100 members that share conserved tripartite motifs and exhibit diverse biological functions. Several TRIM proteins have been shown to restrict viral infections and regulate host cellular innate immune responses. In order to identify TRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for their effects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2). The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced the amounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA. Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBV mRNAs, but also inhibited HBV enhancer I and enhancer II activities. Studies focused on TRIM41 revealed that a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential for TRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3 ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain. Moreover, knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level of HBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA. Our studies have thus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strong evidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatoma cells.
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32
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Shen Y, Lu L, Xu J, Meng W, Qing Y, Liu Y, Zhang B, Hu H. Bortezomib induces apoptosis of endometrial cancer cells through microRNA-17-5p by targeting p21. Cell Biol Int 2013; 37:1114-21. [PMID: 23716467 DOI: 10.1002/cbin.10139] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 04/29/2013] [Indexed: 11/11/2022]
Abstract
Bortezomib suppresses ubiquitin (Ub)-dependent protein degradation and preferentially kills various tumour cells in vitro and in animal models. However, its mechanism of action is not fully understood. We report that bortezomib inhibits the proliferation and proteasomal activity of human endometrial cancer cells and induces G2/M arrest and apoptosis by modulating the miRNA level. By miRNA microarray, iR-17-5p was the most downregulated of all those in HTB-111 and Ishikawa cells after bortezomib treatment. This observation was confirmed by quantitative real-time PCR (qRT-PCR). Target prediction using TargetScan software identified p21 as a potential target for miR-17-5p, which was confirmed by luciferase reporter, qRT-PCR and Western blot assays. The transfection of miR-17-5p mimics or siRNA-p21 reversed the effect of bortezomib on HTB-111 and Ishikawa cells, indicating that miR-17-5p may mediate the function of bortezomib by targeting p21 in endometrial cancer cells. These findings show novel mechanisms by which bortezomib inhibits proliferation and promotes the apoptosis of human endometrial cancer cells.
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Affiliation(s)
- Yuan Shen
- Gynecology and Obstetrics Department of the First Affiliated Hospital of JiNan University, Guangzhou, 510630, China
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33
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Xing C, Fu X, Sun X, Guo P, Li M, Dong JT. Different expression patterns and functions of acetylated and unacetylated Klf5 in the proliferation and differentiation of prostatic epithelial cells. PLoS One 2013; 8:e65538. [PMID: 23755247 PMCID: PMC3673967 DOI: 10.1371/journal.pone.0065538] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 04/25/2013] [Indexed: 12/18/2022] Open
Abstract
KLF5 is a basic transcription factor that regulates multiple biological processes. While it was identified as a putative tumor suppressor in prostate cancer, likely due to its function as an effector of TGF-β in the inhibition of cell proliferation, KLF5 is unacetylated and promotes cell proliferation in the absence of TGF-β. In this study, we evaluated the expression and function of KLF5 in prostatic epithelial homeostasis and tumorigenesis using mouse prostates and human prostate epithelial cells in 3-D culture. Histological and molecular analyses demonstrated that unacetylated-Klf5 was expressed in basal or undifferentiated cells, whereas acetylated-Klf5 was expressed primarily in luminal and/or differentiated cells. Androgen depletion via castration increased both the level of Klf5 expression and the number of Klf5-positive cells in the remaining prostate. Functionally, knockdown of KLF5 in the human RWPE-1 prostate cell line decreased the number of spheres formed in 3-D culture. In addition, knockout of Klf5 in prostate epithelial cells, mediated by probasin promoter-driven Cre expression, did not cause neoplasia but promoted cell proliferation and induced hyperplasia when one Klf5 allele was knocked out. Knockout of both Klf5 alleles however, caused apoptosis rather than cell proliferation in the epithelium. In castrated mice, knockout of Klf5 resulted in more severe shrinkage of the prostate. These results suggest that KLF5 plays a role in the proliferation and differentiation of prostatic epithelial cells, yet loss of KLF5 alone is insufficient to induce malignant transformation in epithelial cells.
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Affiliation(s)
- Changsheng Xing
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Xiaoying Fu
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Department of Pathology, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaodong Sun
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Peng Guo
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Mei Li
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Jin-Tang Dong
- Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China
- Department of Hematology and Medical Oncology, Emory Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
- * E-mail:
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Liu R, Dong JT, Chen C. Role of KLF5 in hormonal signaling and breast cancer development. VITAMINS AND HORMONES 2013; 93:213-25. [PMID: 23810009 DOI: 10.1016/b978-0-12-416673-8.00002-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Steroid hormones, including ovarian steroid hormones progesterone and estrogen and androgen, play vital roles in the development of normal mammary gland and breast cancer via their receptors. How these hormones regulate these physiological and pathological processes remains to be elucidated. Krüppel-like factor 5 (KLF5) is a transcription factor playing significant roles in breast carcinogenesis, whose expression has been shown to be regulated by hormones. In this review, the relationships among hormonal signaling, KLF5, and breast cancer are summarized and discussed.
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Affiliation(s)
- Rong Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
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Oestrogen causes ATBF1 protein degradation through the oestrogen-responsive E3 ubiquitin ligase EFP. Biochem J 2012; 444:581-90. [PMID: 22452784 DOI: 10.1042/bj20111890] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We reported previously that the tumour suppressor ATBF1 (AT motif-binding factor 1) formed an autoregulatory feedback loop with oestrogen-ERα (oestrogen receptor α) signalling to regulate oestrogen-dependent cell proliferation in breast cancer cells. In this loop ATBF1 inhibits the function of oestrogen-ERα signalling, whereas ATBF1 protein levels are fine-tuned by oestrogen-induced transcriptional up-regulation as well as UPP (ubiquitin-proteasome pathway)-mediated protein degradation. In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. EFP interacts with and ubiquitinates ATBF1 protein. Furthermore, we show that EFP is an important factor in oestrogen-induced ATBF1 protein degradation in which some other factors are also involved. In human primary breast tumours the levels of ATBF1 protein are positively correlated with the levels of EFP protein, as both are directly up-regulated ERα target gene products. However, the ratio of ATBF1 protein to EFP protein is negatively correlated with EFP protein levels. Functionally, ATBF1 antagonizes EFP-mediated cell proliferation. These findings not only establish EFP as the E3 ubiquitin ligase for oestrogen-induced ATBF1 protein degradation, but further support the autoregulatory feedback loop between ATBF1 and oestrogen-ERα signalling and thus implicate ATBF1 in oestrogen-dependent breast development and carcinogenesis.
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Castanier C, Zemirli N, Portier A, Garcin D, Bidère N, Vazquez A, Arnoult D. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC Biol 2012; 10:44. [PMID: 22626058 PMCID: PMC3372421 DOI: 10.1186/1741-7007-10-44] [Citation(s) in RCA: 175] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 05/24/2012] [Indexed: 12/24/2022] Open
Abstract
Background During a viral infection, the intracellular RIG-I-like receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-κB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear. Results We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-κB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria. Conclusions These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.
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Affiliation(s)
- Céline Castanier
- INSERM UMR_S 1014, Hôpital Paul Brousse, Bâtiment Lavoisier, 14 avenue Paul Vaillant Couturier, 94807 Villejuif cedex, France
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Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation. Proc Natl Acad Sci U S A 2012; 109:1145-50. [PMID: 22233806 DOI: 10.1073/pnas.1118411109] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation.
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La Rosa P, Acconcia F. Signaling functions of ubiquitin in the 17β-estradiol (E2):estrogen receptor (ER) α network. J Steroid Biochem Mol Biol 2011; 127:223-30. [PMID: 21824518 DOI: 10.1016/j.jsbmb.2011.07.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Revised: 07/23/2011] [Accepted: 07/26/2011] [Indexed: 02/07/2023]
Abstract
Protein posttranslational modifications (PTMs) are signaling alterations that allow coordinating the cellular responses with the changes in the extracellular environment. In this way, the posttranslationally-modified protein becomes a switch node in the transduction network activated by the specific extracellular stimuli. It is now clear that this is the case also for protein ubiquitination: this extremely versatile PTM controls cell physiology through the modulation of protein stability as well as through the modulation of the dynamics of the intracellular signaling cascades. Recent evidence clearly indicates that such a complex scheme appears to be valid also for the 17β-estradiol (E2):estrogen receptor (ER) α signal transduction pathways. Indeed, beside the long standing notion that ERα ubiquitination is required for the regulation of receptor stability, several laboratories, including our own, have clearly indicated that ERα ubiquitination also serves non-degradative functions. This review will reconsider the role of ubiquitination in E2:ERα signaling by particularly highlighting how the functions of the non-degradative ubiquitination impact on ERα activities and contribute to the modulation of E2-dependent physiological processes.
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Affiliation(s)
- Piergiorgio La Rosa
- Department of Biology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146 Rome, Italy
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