KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells

Oncotarget. 2017 Mar 14;8(11):17712-17725. doi: 10.18632/oncotarget.10832.

Abstract

Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to hepatocellular carcinoma (HCC) tumorigenesis and development. Here, we found that miR-615-5p was obviously downregulated in HCC. Furthermore, the deficiency of demethylase KDM4B stimulated the CpG methylation of miR-615-5p promoter and then decreased the miR-615-5p expression. The Ras-related protein RAB24 was found to be downregulated by miR-615-5p. The low level of miR-615-5p increased the expression of RAB24 and facilitated HCC growth and metastasis in vitro and in vivo. Moreover, miR-615-5p suppresses HCC cell growth by influencing cell cycle progression and apoptosis. Downregulation of miR-615-5p and upregulation of RAB24 promotes the epithelial-mesenchymal transition (EMT), adhesion and vasculogenic mimicry (VM) of HCC cells, all of which contribute to cell motility and metastasis. Thus, miR-615-5p, who is downregulated by KDM4B-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting RAB24 expression in HCC. In conclusion, our findings characterize miR-615-5p as an important epigenetically silenced miRNA involved in the Rab-Ras pathway in hepatocellular carcinoma and expand our understanding of the molecular mechanism underlying hepatocarcinogenesis and metastasis.

Keywords: DNA methylation; HCC; gene regulation; metastasis; miRNAs.

MeSH terms

  • Apoptosis / genetics
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Adhesion / genetics
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hep G2 Cells
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • Promoter Regions, Genetic / genetics
  • rab GTP-Binding Proteins / biosynthesis*

Substances

  • MIRN615 microRNA, human
  • MicroRNAs
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4B protein, human
  • RAB24 protein, human
  • rab GTP-Binding Proteins