RNA m ¹ A methylation regulates glycolysis of cancer cells through modulating ATP5D

Abstract

Studies on biological functions of RNA modifications such as <i>N</i>⁶-methyladenosine (m⁶A) in mRNA have sprung up in recent years, while the roles of <i>N</i>¹-methyladenosine (m¹A) in cancer progression remain largely unknown. We find m¹A 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 m¹A demethylase ALKBH3-regulated glycolysis of cancer cells. The m¹A 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. m¹A also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D m¹A by dm¹ACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of m¹A/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA m¹A modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.