N6-methyladenosine regulates glycolysis of cancer cells through PDK4

被引：246

作者：

Li, Zihan ^{[1
,2
]}

Peng, Yanxi ^{[1
,3
]}

Li, Jiexin ^{[1
]}

Chen, Zhuojia ^{[4
]}

Chen, Feng ^{[1
]}

Tu, Jian ^{[2
]}

Lin, Shuibin ^{[5
]}

Wang, Hongsheng ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Key Lab Chiral Mol & Drug Discovery, Guangzhou 510006, Guangdong, Peoples R China

[2] Univ South China, Inst Pharm & Pharmacol, Hengyang 421001, Hunan, Peoples R China

[3] Xiangnan Univ, Dept Basic Med, Chenzhou 423000, Hunan, Peoples R China

[4] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Peoples R China

[5] Sun Yat Sen Univ, Affiliated Hosp 1, Ctr Translat Med, Guangzhou, Peoples R China

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

METHYLTRANSFERASE METTL3 PROMOTES; MESSENGER-RNA METHYLATION; STEM-LIKE CELLS; TRANSCRIPTION FACTORS; BREAST-CANCER; NUCLEAR-RNA; DEMETHYLASE; METABOLISM; EXPRESSION; TRANSLATION;

D O I：

10.1038/s41467-020-16306-5

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 N-6-methyladenosine (m(6)A) modification in mRNA have sprung up in recent years. We find m(6)A can positively regulate the glycolysis of cancer cells. Specifically, m(6)A-sequencing and functional studies confirm that pyruvate dehydrogenase kinase 4 (PDK4) is involved in m(6)A regulated glycolysis and ATP generation. The m(6)A modified 5UTR of PDK4 positively regulates its translation elongation and mRNA stability via binding with YTHDF1/eEF-2 complex and IGF2BP3, respectively. Targeted specific demethylation of PDK4 m(6)A by dm(6)ACRISPR system can significantly decrease the expression of PDK4 and glycolysis of cancer cells. Further, TATA-binding protein (TBP) can transcriptionally increase the expression of Mettl3 in cervical cancer cells via binding to its promoter. In vivo and clinical data confirm the positive roles of m(6)A/PDK4 in tumor growth and progression of cervical and liver cancer. Our study reveals that m(6)A regulates glycolysis of cancer cells through PDK4. p id=Par ysregulation of N6-Methyladenosine (m(6)A) is associated with cancer progression. Here, authors show that m(6)A methylation of pyruvate dehydrogenase kinase 4 (PDK4) positively regulates its mRNA stability and translation, and consequently affects glycolysis in cancer cells

引用

页数：16

共 58 条

[1] Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control [J].

Barbieri, Isaia ;

Tzelepis, Konstantinos ;

Pandolfini, Luca ;

Shi, Junwei ;

Millan-Zambrano, Gonzalo ;

Robson, Samuel C. ;

Aspris, Demetrios ;

Migliori, Valentina ;

Bannister, Andrew J. ;

Han, Namshik ;

De Braekeleer, Etienne ;

Ponstingl, Hannes ;

Hendrick, Alan ;

Vakoc, Christopher R. ;

Vassiliou, George S. ;

Kouzarides, Tony .

NATURE, 2017, 552 (7683) :126-+

[2] Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation [J].

Beretta, L ;

Gingras, AC ;

Svitkin, YV ;

Hall, MN ;

Sonenberg, N .

EMBO JOURNAL, 1996, 15 (03) :658-664

[3] HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g [J].

Cai, Xiaoli ;

Wang, Xiao ;

Cao, Can ;

Gao, Yuen ;

Zhang, Shuqin ;

Yang, Zhe ;

Liu, Yunxia ;

Zhang, Xiaodong ;

Zhang, Weiying ;

Ye, Lihong .

CANCER LETTERS, 2018, 415 :11-19

[4] RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2 [J].

Chen, Mengnuo ;

Wei, Lai ;

Law, Cheuk-Ting ;

Tsang, Felice Ho-Ching ;

Shen, Jialing ;

Cheng, Carol Lai-Hung ;

Tsang, Long-Hin ;

Ho, Daniel Wai-Hung ;

Chiu, David Kung-Chun ;

Lee, Joyce Man-Fong ;

Wong, Carmen Chak-Lui ;

Ng, Irene Oi-Lin ;

Wong, Chun-Ming .

HEPATOLOGY, 2018, 67 (06) :2254-2270

[5] Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs [J].

Chen, Zhuojia ;

Qi, Meijie ;

Shen, Bin ;

Luo, Guanzheng ;

Wu, Yingmin ;

Li, Jiexin ;

Lu, Zhike ;

Zheng, Zhong ;

Dai, Qing ;

Wang, Hongsheng .

NUCLEIC ACIDS RESEARCH, 2019, 47 (05) :2533-2545

[6] mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis [J].

Choe, Junho ;

Lin, Shuibin ;

Zhang, Wencai ;

Liu, Qi ;

Wang, Longfei ;

Ramirez-Moya, Julia ;

Du, Peng ;

Kim, Wantae ;

Tang, Shaojun ;

Sliz, Piotr ;

Santisteban, Pilar ;

George, Rani E. ;

Richards, William G. ;

Wong, Kwok-Kin ;

Locker, Nicolas ;

Slack, Frank J. ;

Gregory, Richard I. .

NATURE, 2018, 561 (7724) :556-+

[7] MiR-33a suppresses proliferation of NSCLC cells via targeting METTL3 mRNA [J].

Du, Minjun ;

Zhang, Yanjiao ;

Mao, Yousheng ;

Mou, Juwei ;

Zhao, Jun ;

Xue, Qi ;

Wang, Dali ;

Huang, Jinfeng ;

Gao, Shugeng ;

Gao, Yushun .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2017, 482 (04) :582-589

[8] Translational Activation of Snail1 and Other Developmentally Regulated Transcription Factors by YB-1 Promotes an Epithelial-Mesenchymal Transition [J].

Evdokimova, Valentina ;

Tognon, Cristina ;

Ng, Tony ;

Ruzanov, Peter ;

Melnyk, Natalya ;

Fink, Dieter ;

Sorokin, Alexey ;

Ovchinnikov, Lev P. ;

Davicioni, Elai ;

Triche, Timothy J. ;

Sorensen, Poul H. B. .

CANCER CELL, 2009, 15 (05) :402-415

[9] Tumor glycolysis as a target for cancer therapy: progress and prospects [J].

Ganapathy-Kanniappan, Shanmugasundaram ;

Geschwind, Jean-Francois H. .

MOLECULAR CANCER, 2013, 12

[10] HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation [J].

Gordan, John D. ;

Thompson, Craig B. ;

Simon, M. Celeste .

CANCER CELL, 2007, 12 (02) :108-113

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