MYC Promotes Cancer Progression by Modulating m6A Modifications to Suppress Target Gene Translation

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or -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 (m6A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m6A controls the translation of MRG mRNA via the specific m6A 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 m6A modifications in selected MRG transcripts promotes cancer progression.