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 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.

Automated summary

The oncogene MYC promotes cancer progression by down-regulating N6-methyladenosine (m(6)A) modification preferentially in transcripts of MYC-repressed genes (MRGs). This alteration leads to the activation of ALKBH5 expression and reduction of m(6)A levels in specific MRGs, controlling their translation through the m(6)A reader YTHDF3. Ultimately, inhibiting ALKBH5 or overexpressing SPI1 or PHF12 effectively suppresses the growth of MYC-deregulated B-cell lymphomas.