据报道，大量的circRNA在结直肠癌（CRC）中发挥着重要作用，但癌症中circRNA表达异常的原因仍然难以捉摸。在这里，我们发现m7G RNA修饰在一些circRNA中富集，这些circRNA中的m7G修饰是由METTL1催化的，并且GG基序是circRNA中m7G修饰的主要位点偏好。我们进一步证实METTL1在CRC中发挥促癌作用。然后我们筛选了一种高表达的circRNA，称为circKDM1A，发现METTL1通过m7G修饰阻止了circKDM1A的降解。 CircKDM1A在体内外被进一步验证可促进CRC的增殖、侵袭和迁移。 m7G位点突变后其促癌能力减弱。 CircKDM1A 被证实可通过上调 PDK1 激活 AKT 通路，从而促进 CRC 进展。这些结果表明 m7G 修饰的 circRNA 通过激活 AKT 通路促进 CRC 进展。我们的研究揭示了 METTL1 介导的 m7G 修饰在调节 circRNA 稳定性和癌症进展中的重要生理功能和机制。© 2024。作者。

Plenty of circRNAs have been reported to play an important role in colorectal cancer (CRC), while the reason of abnormal circRNA expression in cancer still keep elusive. Here, we found that m7G RNA modifications were enriched in some circRNAs, these m7G modifications in circRNAs were catalyzed by METTL1, and the GG motif was the main site preference for m7G modifications in circRNAs. We further confirmed that METTL1 played a cancer-promoting role in CRC. We then screened a highly expressed circRNA, called circKDM1A, and found that METTL1 prevented the degradation of circKDM1A by m7G modification. CircKDM1A was further verified to promote proliferation, invasion and migration of CRC in vivo and in vitro. Its cancer-promoting ability was weakened after the m7G site mutation. CircKDM1A was verified to activate AKT pathway by upregulating PDK1, consequently promoting CRC progression. These results suggest that m7G-modified circRNA promotes CRC progression via activating AKT pathway. Our study uncovers an essential physiological function and mechanism of METTL1-mediated m7G modification in the regulation of circRNA stability and cancer progression.© 2024. The Author(s).