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

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.