RNA m 1 A 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.