The importance of RNA methylation in biological processes is an emerging focus of investigation. We report that altering m⁶A levels by silencing either N⁶-adenosine methyltransferase METTL14 (methyltransferase-like 14) or demethylase ALKBH5 (ALKB homolog 5) inhibits cancer growth and invasion. METTL14/ALKBH5 mediate their protumorigenic function by regulating m⁶A levels of key epithelial-mesenchymal transition and angiogenesis-associated transcripts, including transforming growth factor-β signaling pathway genes. Using MeRIP-seq (methylated RNA immunoprecipitation sequencing) analysis and functional studies, we find that these target genes are particularly sensitive to changes in m⁶A modifications, as altered m⁶A status leads to aberrant expression of these genes, resulting in inappropriate cell cycle progression and evasion of apoptosis. Our results reveal that METTL14 and ALKBH5 determine the m⁶A status of target genes by controlling each other's expression and by inhibiting m⁶A reader YTHDF3 (YTH N⁶-methyladenosine RNA binding protein 3), which blocks RNA demethylase activity. Furthermore, we show that ALKBH5/METTL14 constitute a positive feedback loop with RNA stability factor HuR to regulate the stability of target transcripts. We discover that hypoxia alters the level/activity of writers, erasers, and readers, leading to decreased m⁶A and consequently increased expression of target transcripts in cancer cells. This study unveils a previously undefined role for m⁶A in cancer and shows that the collaboration among writers-erasers-readers sets up the m⁶A threshold to ensure the stability of progrowth/proliferation-specific genes, and protumorigenic stimulus, such as hypoxia, perturbs that m⁶A threshold, leading to uncontrolled expression/activity of those genes, resulting in tumor growth, angiogenesis, and progression.

中文翻译：

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m6A 的作者、读者和橡皮擦之间的串扰调节癌症的生长和进展。

RNA甲基化在生物过程中的重要性是一个新兴的研究重点。我们报告说，通过沉默N ⁶ -腺苷甲基转移酶 METTL14（甲基转移酶样 14）或脱甲基酶 ALKBH5（ALKB 同源物 5）来改变 m ⁶ A 水平可抑制癌症生长和侵袭。METTL14/ALKBH5 通过调节关键上皮-间充质转化和血管生成相关转录物（包括转化生长因子-β 信号通路基因）的m ⁶ A 水平来介导它们的促肿瘤发生功能。使用 MeRIP-seq（甲基化 RNA 免疫沉淀测序）分析和功能研究，我们发现这些靶基因对 m ⁶ A 修饰的变化特别敏感，因为 m⁶ A 状态会导致这些基因的异常表达，从而导致细胞周期进程不当和细胞凋亡的逃避。我们的结果表明，METTL14 和 ALKBH5通过控制彼此的表达和抑制 m ⁶ A 阅读器 YTHDF3（YTH N ⁶ - 甲基腺苷RNA 结合蛋白 3）来确定靶基因的 m ⁶ A 状态，后者阻断 RNA 脱甲基酶活性。此外，我们表明 ALKBH5/METTL14 与 RNA 稳定因子 HuR 构成一个正反馈回路，以调节目标转录物的稳定性。我们发现缺氧会改变书写者、橡皮擦和阅读器的水平/活动，导致 m ⁶A 并因此增加了癌细胞中靶转录物的表达。这项研究揭示了 m ⁶ A 在癌症中的先前未定义的作用，并表明作者-橡皮擦-读者之间的合作设置了 m ⁶ A 阈值，以确保促生长/增殖特异性基因和促肿瘤刺激（如缺氧）的稳定性，扰乱 m ⁶ A 阈值，导致这些基因的表达/活性不受控制，导致肿瘤生长、血管生成和进展。