Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China.
Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2119038119. doi: 10.1073/pnas.2119038119. Epub 2022 Jul 8.
Studies on biological functions of RNA modifications such as -methyladenosine (mA) in mRNA have sprung up in recent years, while the roles of -methyladenosine (mA) in cancer progression remain largely unknown. We find mA demethylase ALKBH3 can regulate the glycolysis of cancer cells via a demethylation activity dependent manner. Specifically, sequencing and functional studies confirm that ATP5D, one of the most important subunit of adenosine 5'-triphosphate synthase, is involved in mA demethylase ALKBH3-regulated glycolysis of cancer cells. The mA modified A71 at the exon 1 of ATP5D negatively regulates its translation elongation via increasing the binding with YTHDF1/eRF1 complex, which facilitates the release of message RNA (mRNA) from ribosome complex. mA also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D mA by dmACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of mA/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA mA modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.
近年来，关于 RNA 修饰（如 mRNA 中的 -甲基腺苷（mA））的生物学功能的研究如雨后春笋般涌现，而 -甲基腺苷（mA）在癌症进展中的作用在很大程度上仍不清楚。我们发现 mA 去甲基化酶 ALKBH3 可以通过去甲基化活性依赖性方式调节癌细胞的糖酵解。具体而言，测序和功能研究证实，三磷酸腺苷合酶的最重要亚基之一 ATP5D 参与了 mA 去甲基化酶 ALKBH3 调节的癌细胞糖酵解。在 ATP5D 的外显子 1 中，mA 修饰的 A71 通过增加与 YTHDF1/eRF1 复合物的结合，负调控其翻译延伸，从而促进信使 RNA（mRNA）从核糖体复合物中释放。mA 还调节 E2F1 的 mRNA 稳定性，E2F1 直接与 ATP5D 启动子结合以启动其转录。通过 dmACRISPR 系统靶向特异性去甲基化 ATP5D mA 可以显著增加 ATP5D 的表达和癌细胞的糖酵解。体内数据证实了 mA/ATP5D 在肿瘤生长和癌症进展中的作用。我们的研究揭示了 mRNA mA 修饰和细胞代谢之间的串扰，这扩展了对这些相互作用的理解，这些相互作用对于癌症治疗应用至关重要。
