MYC promotes cancer progression by modulating m6A modifications to suppress target gene translation

• Published in: EMBO reports 2021-03, Vol.22 (3), p.n/a
• Main Authors: Wu, Gongwei, Suo, Caixia, Yang, Ying, Shen, Shengqi, Sun, Linchong, Li, Shi-Ting, Zhou, Yingli, Yang, Dongdong, Wang, Yan, Cai, Yongping, Wang, Nana, Zhang, Huafeng, Yang, Yun-Gui, Cao, Jie, Gao, Ping
• Format: Article
• Language: English
• Subjects: ALKBH5; Cancer; Deregulation; EMBO03; EMBO09; EMBO36; Gene expression; Genes; Kinases; Lymphoma; m6A; MYC; Myc protein; MYC‐repressed genes; N6-methyladenosine; oncogenesis; RNA modification; Transcription; Translation
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202051519

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m 6 A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m 6 A levels in the mRNA of the selected MRGs SPI1 and PHF12 . We also show that MYC-regulated m 6 A controls the translation of MRG mRNA via the specific m 6 A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo . Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m 6 A modifications in selected MRG transcripts promotes cancer progression. SYNOPSIS MYC suppresses gene expression by indirectly altering m 6 A modifications in transcripts of MYC-repressed genes via ALKBH5 to promote cancer progression. MYC indirectly down-regulates m 6 A levels in mRNA and inhibits protein expression of selected MRG transcripts. MYC transcriptionally activates the m 6 A demethylases ALKBH5 and FTO. ALKBH5 removes m 6 A and YTHDF3 binds m 6 A-modified mRNAs to regulate the translation of SPI1/PHF12. The MYC-ALKBH5-m 6 A-SPI1/PHF12 axis is critical for cancer progression. Graphical Abstract MYC suppresses gene expression by indirectly altering m 6 A modifications in transcripts of MYC-repressed genes via ALKBH5 to promote cancer progression.