RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D

Studies on biological functions of RNA modifications such as N-6-methyladenosine (m(6)A) in mRNA have sprung up in recent years, while the roles of N-1-methyladenosine (m(1)A) in cancer progression remain largely unknown. We find m(1)A 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 m(1)A demethylase ALKBH3-regulated glycolysis of cancer cells. The m(1)A 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. m(1)A also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D m(1)A by dm(1) ACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of m(1)A/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA m(1)A modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.