TY - JOUR
T1 - Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis
AU - Wu, Shan Ying
AU - Lan, Sheng Hui
AU - Liu, Hsiao Sheng
N1 - Publisher Copyright:
© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2019/4/3
Y1 - 2019/4/3
N2 - Overexpressed CCND1 (cyclin D1) is associated with hepatocellular carcinoma (HCC) and we used 147 tumor tissue samples from HCC patients and 3 murine models to reveal an inverse correlation between low autophagic activity and high CCND1 expression. These 2 phenomena in combination correlated with poor overall survival in HCC patients. Mechanistic analysis showed that activated autophagy triggered CCND1 ubiquitination followed by SQSTM1 (sequestosome 1)-mediated selective phagophore recruitment, autophagosome formation, fusion with a lysosome, and degradation. Functional studies revealed that autophagy-selective degradation of CCND1 suppresses DNA synthesis, cell proliferation, and colony, and liver tumor formation by arresting the cell cycle at the G 1 phase. Most importantly, diverse pharmacological inducers (rapamycin and amiodarone) effectively suppress tumor growth in orthotopic liver tumor and subcutaneous tumor xenograft models. In conclusion, we have demonstrated a link between degradative autophagy and the cell cycle regulator CCND1, and have discovered the underlying mechanism by which the autophagic degradation machinery regulates the turnover of the cell-cycle regulator CCND1, which in turn affects HCC tumorigenesis. Abbreviations: CCDN1: cyclin D1; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; SQSTM1: sequestosome 1.
AB - Overexpressed CCND1 (cyclin D1) is associated with hepatocellular carcinoma (HCC) and we used 147 tumor tissue samples from HCC patients and 3 murine models to reveal an inverse correlation between low autophagic activity and high CCND1 expression. These 2 phenomena in combination correlated with poor overall survival in HCC patients. Mechanistic analysis showed that activated autophagy triggered CCND1 ubiquitination followed by SQSTM1 (sequestosome 1)-mediated selective phagophore recruitment, autophagosome formation, fusion with a lysosome, and degradation. Functional studies revealed that autophagy-selective degradation of CCND1 suppresses DNA synthesis, cell proliferation, and colony, and liver tumor formation by arresting the cell cycle at the G 1 phase. Most importantly, diverse pharmacological inducers (rapamycin and amiodarone) effectively suppress tumor growth in orthotopic liver tumor and subcutaneous tumor xenograft models. In conclusion, we have demonstrated a link between degradative autophagy and the cell cycle regulator CCND1, and have discovered the underlying mechanism by which the autophagic degradation machinery regulates the turnover of the cell-cycle regulator CCND1, which in turn affects HCC tumorigenesis. Abbreviations: CCDN1: cyclin D1; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; SQSTM1: sequestosome 1.
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U2 - 10.1080/15548627.2019.1569918
DO - 10.1080/15548627.2019.1569918
M3 - Comment/debate
C2 - 30646811
AN - SCOPUS:85060908954
SN - 1554-8627
VL - 15
SP - 729
EP - 730
JO - Autophagy
JF - Autophagy
IS - 4
ER -