RNA mA methylation regulates glycolysis of cancer cells through modulating ATP5D.

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.