RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D

被引:50
|
作者
Wu, Yingmin [1 ,2 ]
Chen, Zhuojia [3 ]
Xie, Guoyou [1 ]
Zhang, Haisheng [1 ]
Wang, Zhaotong [1 ]
Zhou, Jiawang [1 ]
Chen, Feng [1 ]
Li, Jiexin [1 ]
Chen, Likun [3 ]
Niu, Hongxin [4 ]
Wang, Hongsheng [1 ]
机构
[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Design & Evaluat, Guangzhou 510006, Peoples R China
[2] Guizhou Med Univ, Transformat Engn Res Ctr Chron Dis Diag & Treatme, Sch Basic Med, Dept Physiol, Guiyang 550025, Guizhou, Peoples R China
[3] Sun Yat Sen Univ, State Key Lab Oncol South China, Canc Ctr, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Peoples R China
[4] Southern Med Univ, Zhujiang Hosp, Dept Gen Practice, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
m(1)A; metabolism; ATP5D; cancer cell; MESSENGER-RNA; METHYLOME; HALLMARKS;
D O I
10.1073/pnas.2119038119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:12
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