c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma
Open Access
- 3 September 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 59 (5), 1850-1863
- https://doi.org/10.1002/hep.26720
Abstract
The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c‐Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR‐101, an important tumor‐suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c‐Myc‐mediated manner. miR‐101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double‐negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR‐101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR‐101 by inhibition of PRC2 activation. In addition, co‐overexpression of c‐Myc and EZH2 in HCC samples was closely associated with lower expression of miR‐101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). Conclusions: c‐Myc collaborates with EZH2‐containing PRC2 complex in silencing tumor‐suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC. (Hepatology 2014;59:1850–1863)Keywords
This publication has 44 references indexed in Scilit:
- MYC on the Path to CancerCell, 2012
- Molecular Mechanisms of Liver CancerAnti-Cancer Agents in Medicinal Chemistry, 2011
- microRNA involvement in hepatocellular carcinoma.Anti-Cancer Agents in Medicinal Chemistry, 2011
- MicroRNAs in Cancer: Small Molecules With a Huge ImpactJournal of Clinical Oncology, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Impaired microRNA processing enhances cellular transformation and tumorigenesisNature Genetics, 2007
- MicroRNA Signatures in Human CancersNature Reviews Cancer, 2006
- A microRNA expression signature of human solid tumors defines cancer gene targetsProceedings of the National Academy of Sciences of the United States of America, 2006
- MicroRNA expression profiles classify human cancersNature, 2005
- Global Cancer Statistics, 2002CA: A Cancer Journal for Clinicians, 2005