The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

Qian Gao; Jin Zheng; Zegui Ni; Pengli Sun; Congcong Yang; Maosheng Cheng; Mingqing Wu; Xiuhong Zhang; Lin Yuan; Yingyin Zhang; Yang Li

doi:10.1155/2020/8849218

The m⁶A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

Stem Cells Int. 2020 Jul 2:2020:8849218. doi: 10.1155/2020/8849218. eCollection 2020.

Authors

Affiliations

¹ Department of Genetics, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China.
² Department of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, No. 100 Hai Ning Road, Hongkou District, Shanghai 200080, China.

Abstract

The dynamic N⁶-methyladenosine (m⁶A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m⁶A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m⁶A abundance and the expression of m⁶A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m⁶A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m⁶A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.