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 (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.

中文翻译：

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MYC 通过调节 m6A 修饰以抑制靶基因翻译来促进癌症进展

MYC 癌蛋白以转录依赖性或转录非依赖性方式激活和抑制基因表达。mRNA 的修饰成为关键的基因表达调控关系。我们试图确定 MYC 是否会改变 mRNA 修饰，并在此报告 MYC 通过优先下调 MYC 抑制基因 (MRG) 子集的转录本中的N6-甲基腺苷 (m ^{6 A) 来促进癌症进展。}我们发现 MYC 激活 ALKBH5 的表达并降低所选 MRG SPI1和PHF12的 mRNA 中的 m ⁶ A 水平。我们还表明 MYC 调节的 m ^{6 A 通过特定的 m 6}控制 MRG mRNA 的翻译阅读器 YTHDF3。最后，我们发现抑制 ALKBH5 或 SPI1 或 PHF12 的过表达，在体外和体内都有效地抑制了 MYC 失调的 B 细胞淋巴瘤的生长。我们的研究结果揭示了一种新机制，MYC 通过改变选定 MRG 转录物中的 m ⁶ A 修饰来抑制基因表达，从而促进癌症进展。