Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis

Shan Ying Wu, Sheng Hui Lan, Hsiao-Sheng Liu

Research output: Contribution to journalComment/debate

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)729-730
Number of pages2
JournalAutophagy
Volume15
Issue number4
DOIs
Publication statusPublished - 2019 Apr 3

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Cyclin D1
Autophagy
Hepatocellular Carcinoma
Carcinogenesis
Cell Cycle
Neoplasms
Amiodarone
Ubiquitination
Liver
Sirolimus
Lysosomes
Heterografts
Hepatitis B virus
Hepacivirus
Cell Proliferation
Pharmacology
Survival
DNA
Growth

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

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title = "Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis",
abstract = "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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Degradative autophagy selectively regulates CCND1 (cyclin D1) and MIR224, two oncogenic factors involved in hepatocellular carcinoma tumorigenesis. / Wu, Shan Ying; Lan, Sheng Hui; Liu, Hsiao-Sheng.

In: Autophagy, Vol. 15, No. 4, 03.04.2019, p. 729-730.

Research output: Contribution to journalComment/debate

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AU - Lan, Sheng Hui

AU - Liu, Hsiao-Sheng

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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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