Long non-coding RNA RBMY2FP promotes proliferation of male hepatocellular carcinoma by directing DNA methylation and activating RBMY1A1 via DNMT1

// Feng Liu 1, 2, * , Fu Yang 1, * , Xia Wu 3, * , Jin-Feng Huang 1, * , Ji-Hang Yuan 1 , Qi-fei Tao 4 , Gui-hua Jiang 3 , Jia-sheng Zheng 5 , Shu-Han Sun 1 1 Department of Medical Genetics, Second Military Medical University, Shanghai, 200433, China 2 Reproductive Medical Center, Obstetrics and Gynecology of Navy PLA General Hospital, Beijing 100048, China 3 Department of Infectious Diseases, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China 4 The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, 200433, China 5 Center of Intervention Oncology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China * These authors have contributed equally to this work Correspondence to: Shu-Han Sun, email: shsun@vip.sina.com Jia-sheng Zheng, email: zhengjiasheng6@163.com Keywords: long non-coding RNA, RBMY, DNMT1, DNA methylation, HCC gender disparity Received: November 25, 2015      Accepted: June 29, 2016      Published: July 30, 2016 ABSTRACT Sexual dimorphism is a major issue in hepatocellular carcinoma (HCC), with significantly higher incidence in males. We screened male specific Y chromosome transcripts through RNA sequence and discovered a long non-coding RNA RBMY2FP (RNA binding motif protein, Y-linked, family 2, member F pseudogene, lnc-RBMY2FP) that is specifically expressed in about 1/3 male HCC tissues, with no expression in adjacent livers. Positive expression of lnc-RBMY2FP in male HCC is related to poor patient survival. Lnc-RBMY2FP enhances HCC cell growth, proliferation and tumor stemness both in vitro and in vivo . Mechanistically, lnc-RBMY2FP interacts with DNMT1 and hampers its binding onto promoters of RBMY gene family. Thus, maintenance of promoter methylation status is disturbed because of inhibition of DNMT1 activity, leading to increased expression of RBMY1A1 protein and enhanced hepatocarcinogenesis. The finding of lnc-RBMY2FP may partially explain the male preference of HCC and potentially contribute to HCC treatment.