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

// Zheng Chen 1, * , Xiangling Wang 1, * , Ruiyan Liu 1, 2, * , Lin Chen 1 , Jianying Yi 1 , Bing Qi 1 , Zeyu Shuang 3 , Min Liu 1 , Xin Li 1 , Shengping Li 3 , Hua Tang 1 1 Tianjin Life Science Research Center and School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China 2 Department of Laboratory Medicine, the First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China 3 State Key Laboratory of Oncology in Southern China, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Hua Tang, email: htang2002@yahoo.com Keywords: DNA methylation, miRNAs, metastasis, HCC, gene regulation Received: October 20, 2015     Accepted: June 17, 2016     Published: July 25, 2016 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.