title: c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma.
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.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China; Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: Si-Jun
authors.initials: SJ
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Yang
authors.forename: Wei-Hong
authors.initials: WH
authors.lastname: Wen
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Rui-An
authors.initials: RA
authors.lastname: Wang
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Meng
authors.forename: Yong-Zhan
authors.initials: YZ
authors.lastname: Nie
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
authors.forename: Si-Yi
authors.initials: SY
authors.lastname: Chen
authors.forename: Li-Bo
authors.initials: LB
authors.lastname: Yao
authors.forename: Dai-Ming
authors.initials: DM
authors.lastname: Fan
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D054387:Receptors, CXCR / Q000502:physiology
chemical_list: C501896:ACKR3 protein, human; C534072:MIRN101 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D054387:Receptors, CXCR; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2