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

Shan Ying Wu, Sheng Hui Lan, Shang Rung Wu, Yen Chi Chiu, Xi Zhang Lin, Ih Jen Su, Ting Fen Tsai, Chia Jui Yen, Tsung Hsueh Lu, Fu Wen Liang, Chung Yi Li, Huey Jen Su, Chun Li Su, Hsiao Sheng Liu

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17 Citations (Scopus)

Abstract

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).

Original languageEnglish
Pages (from-to)141-154
Number of pages14
JournalHepatology
Volume68
Issue number1
DOIs
Publication statusPublished - 2018 Jul 1

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ASJC Scopus subject areas

  • Hepatology

Cite this

Wu, S. Y., Lan, S. H., Wu, S. R., Chiu, Y. C., Lin, X. Z., Su, I. J., Tsai, T. F., Yen, C. J., Lu, T. H., Liang, F. W., Li, C. Y., Su, H. J., Su, C. L., & Liu, H. S. (2018). Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system. Hepatology, 68(1), 141-154. https://doi.org/10.1002/hep.29781