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RNA m¹A methylation regulates glycolysis of cancer cells through modulating ATP5D.

ABSTRACT: Studies on biological functions of RNA modifications such as N⁶-methyladenosine (m⁶A) in mRNA have sprung up in recent years, while the roles of N¹-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.

SUBMITTER: Wu Y

PROVIDER: S-EPMC9282374 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D.

Wu Yingmin Y Chen Zhuojia Z Xie Guoyou G Zhang Haisheng H Wang Zhaotong Z Zhou Jiawang J Chen Feng F Li Jiexin J Chen Likun L Niu Hongxin H Wang Hongsheng H

Proceedings of the National Academy of Sciences of the United States of America 20220708 28

Studies on biological functions of RNA modifications such as N6-methyladenosine (m6A) in mRNA have sprung up in recent years, while the roles of N1-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 ...[more]

PMID: 35867754

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Project description:Macroautophagy/autophagy is indispensable for testosterone synthesis in Leydig cells (LCs), and here we report a negative association between m6A modification and autophagy in LCs during testosterone synthesis. A gradual decrease of METTL14 (methyltransferase like 14) and an increase of ALKBH5 (alkB homolog 5, RNA demethylase) were observed in LCs during their differentiation from stem LCs to adult LCs. These events led to reduced mRNA methylation levels of N6-methyladenosine (m6A) and enhanced autophagy in LCs. Similar regulation of METTL14, ALKBH5, and m6A was also observed in LCs upon treatment with human chorionic gonadotropin (HsCG). Mechanistically, m6A modification promoted translation of PPM1A (protein phosphatase 1A, magnesium dependent, alpha isoform), a negative AMP-activated protein kinase (AMPK) regulator, but decreased expression of CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, beta), a positive AMPK regulator, by reducing its RNA stability. Thus, m6A modification resulted in reduced AMPK activity and subsequent autophagy inhibition. We further demonstrated that ALKBH5 upregulation by HsCG was dependent on enhanced binding of the transcriptional factor CEBPB (CCAAT/enhancer binding protein [C/EBP], beta) and the TFEB (transcription factor EB) to its gene promoter. Moreover, HsCG treatment decreased METTL14 by reducing its stability. Collectively, this study highlights a vital role of m6A RNA methylation in the modulation of testosterone synthesis in LCs, providing insight into novel therapeutic strategies by exploiting m6A RNA methylation as targets for treating azoospermatism and oligospermatism patients with reduction in serum testosterone.Abbreviations: 3-MA: 3-methyladenine; ACTB: Actin, beta; ALKBH5: alkB homolog 5, RNA demethylase; AMPK: AMP-activated protein kinase; BafA1: bafilomycin A1; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; CEBPB: CCAAT/enhancer-binding protein (C/EBP), beta; ChIP: chromatin immunoprecipitation; FTO: fat mass and obesity associated; HsCG: human chorionic gonadotropin; HSD3B: 3β-hydroxysteroid dehydrogenase; LCs: Leydig cells; m6A: N6-methyladenosine; METTL14: methyltransferase like 14; METTL3: methyltransferase like 3; MTOR: mechanistic target of rapamycin kinase; PPM1A: protein phosphatase 1A, magnesium dependent, alpha isoform; PRKAA: 5'-AMP-activated protein kinase catalytic subunit alpha; SQSTM1: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TFEB: transcription factor EB; ULK1: unc-51-like kinase 1; WTAP: Wilms tumor 1-associating protein; YTHDF: YTH N6-methyladenosine RNA binding protein.

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RNA m¹A methylation regulates glycolysis of cancer cells through modulating ATP5D.

Publications

RNA m<sup>1</sup>A methylation regulates glycolysis of cancer cells through modulating ATP5D.

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