N6 -methyladenosine-modified FAM111A-DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A.

Jian Pu, Zuoming Xu, Youguan Huang, Jiahui Nian, Meng Yang, Quan Fang, Qing Wei, Zihua Huang, Guoman Liu, Jianchu Wang, Xianjian Wu, Huamei Wei

Cancer science 2023 Sep

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As an epitranscriptomic modulation manner, N6 -methyladenosine (m6 A) modification plays important roles in various diseases, including hepatocellular carcinoma (HCC). m6 A modification affects the fate of RNAs. The potential contributions of m6 A to the functions of RNA still need further investigation. In this study, we identified long noncoding RNA FAM111A-DT as an m6 A-modified RNA and confirmed three m6 A sites on FAM111A-DT. The m6 A modification level of FAM111A-DT was increased in HCC tissues and cell lines, and increased m6 A level was correlated with poor survival of HCC patients. m6 A modification increased the stability of FAM111A-DT transcript, whose expression level showed similar clinical relevance to that of the m6 A level of FAM111A-DT. Functional assays found that only m6 A-modified FAM111A-DT promoted HCC cellular proliferation, DNA replication, and HCC tumor growth. Mutation of m6 A sites on FAM111A-DT abolished the roles of FAM111A-DT. Mechanistic investigations found that m6 A-modified FAM111A-DT bound to FAM111A promoter and also interacted with m6 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 m6 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 m6 A-modified FAM111A-DT in HCC. In summary, the m6 A-modified FAM111A-DT/YTHDC1/KDM3B/FAM111A regulatory axis promoted HCC growth and represented a candidate therapeutic target for HCC. © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Citation

Jian Pu, Zuoming Xu, Youguan Huang, Jiahui Nian, Meng Yang, Quan Fang, Qing Wei, Zihua Huang, Guoman Liu, Jianchu Wang, Xianjian Wu, Huamei Wei. N6 -methyladenosine-modified FAM111A-DT promotes hepatocellular carcinoma growth via epigenetically activating FAM111A. Cancer science. 2023 Sep;114(9):3649-3665