N(6) ‐methyladenosine‐modified FAM111A‐DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A

As an epitranscriptomic modulation manner, N(6)‐methyladenosine (m(6)A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m(6)A modification affects the fate of RNAs. The potential contributions of m(6)A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A‐DT as an m(6)A‐modified RNA and confirmed three m(6)A sites on FAM111A‐DT. The m(6)A modification level of FAM111A‐DT was increased in HCC tissues and cell lines, and increased m(6)A level was correlated with poor survival of HCC patients. m(6)A modification increased the stability of FAM111A‐DT transcript, whose expression level showed similar clinical relevance to that of the m(6)A level of FAM111A‐DT. Functional assays found that only m(6)A‐modified FAM111A‐DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m(6)A sites on FAM111A‐DT abolished the roles of FAM111A‐DT. Mechanistic investigations found that m(6)A‐modified FAM111A‐DT bound to FAM111A promoter and also interacted with m(6)A reader YTHDC1, which further bound and recruited histone demethylase KDM3B to FAM111A promoter, leading to the reduction of the repressive histone mark H3K9me2 and transcriptional activation of FAM111A. The expression of FAM111A was positively correlated with the m(6)A level of FAM111A‐DT, and the expression of methyltransferase complex, YTHDC1, and KDM3B in HCC tissues. Depletion of FAM111A largely attenuated the roles of m(6)A‐modified FAM111A‐DT in HCC. In summary, the m(6)A‐modified FAM111A‐DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC.