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Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present...

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Autores principales: Wu, Shan‐Ying, Lan, Sheng‐Hui, Wu, Shang‐Rung, Chiu, Yen‐Chi, Lin, Xi‐Zhang, Su, Ih‐Jen, Tsai, Ting‐Fen, Yen, Chia‐Jui, Lu, Tsung‐Hsueh, Liang, Fu‐Wen, Li, Chung‐Yi, Su, Huey‐Jen, Su, Chun‐Li, Liu, Hsiao‐Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055810/
https://www.ncbi.nlm.nih.gov/pubmed/29328502
http://dx.doi.org/10.1002/hep.29781
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author Wu, Shan‐Ying
Lan, Sheng‐Hui
Wu, Shang‐Rung
Chiu, Yen‐Chi
Lin, Xi‐Zhang
Su, Ih‐Jen
Tsai, Ting‐Fen
Yen, Chia‐Jui
Lu, Tsung‐Hsueh
Liang, Fu‐Wen
Li, Chung‐Yi
Su, Huey‐Jen
Su, Chun‐Li
Liu, Hsiao‐Sheng
author_facet Wu, Shan‐Ying
Lan, Sheng‐Hui
Wu, Shang‐Rung
Chiu, Yen‐Chi
Lin, Xi‐Zhang
Su, Ih‐Jen
Tsai, Ting‐Fen
Yen, Chia‐Jui
Lu, Tsung‐Hsueh
Liang, Fu‐Wen
Li, Chung‐Yi
Su, Huey‐Jen
Su, Chun‐Li
Liu, Hsiao‐Sheng
author_sort Wu, Shan‐Ying
collection PubMed
description Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K(33‐238)R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154).
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spelling pubmed-60558102018-07-30 Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system Wu, Shan‐Ying Lan, Sheng‐Hui Wu, Shang‐Rung Chiu, Yen‐Chi Lin, Xi‐Zhang Su, Ih‐Jen Tsai, Ting‐Fen Yen, Chia‐Jui Lu, Tsung‐Hsueh Liang, Fu‐Wen Li, Chung‐Yi Su, Huey‐Jen Su, Chun‐Li Liu, Hsiao‐Sheng Hepatology Original Articles Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K(33‐238)R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154). John Wiley and Sons Inc. 2018-03-23 2018-07 /pmc/articles/PMC6055810/ /pubmed/29328502 http://dx.doi.org/10.1002/hep.29781 Text en © 2018 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Wu, Shan‐Ying
Lan, Sheng‐Hui
Wu, Shang‐Rung
Chiu, Yen‐Chi
Lin, Xi‐Zhang
Su, Ih‐Jen
Tsai, Ting‐Fen
Yen, Chia‐Jui
Lu, Tsung‐Hsueh
Liang, Fu‐Wen
Li, Chung‐Yi
Su, Huey‐Jen
Su, Chun‐Li
Liu, Hsiao‐Sheng
Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title_full Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title_fullStr Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title_full_unstemmed Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title_short Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system
title_sort hepatocellular carcinoma–related cyclin d1 is selectively regulated by autophagy degradation system
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055810/
https://www.ncbi.nlm.nih.gov/pubmed/29328502
http://dx.doi.org/10.1002/hep.29781
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