METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression

Journal of Experimental & Clinical Cancer Research

Research

Yike Cai¹  Guan-Min Jiang²  Chun-Lei Sun³  Bin Shi³  Wei Wei⁴  Shuang Zhang⁴  Chen Wang⁴  Hao Wang⁴  Bing He⁴  Yun-Fei Fei⁴  Wen Zhong⁵  Hou-Shun Zhang⁵  Zhong-Yuan Zhang⁶ 

[1]Center for Certification and Evaluation, Guangdong Drug Administration, Guangzhou, China

[2]Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

[3]Department of General Surgery, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China

[4]Department of Laboratory Medicine, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China

[5]Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China

[6]Department of Pathology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China

[7]Department of Radiology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China

关键词: Colorectal cancer;    m6A;    METTL16;    SOGA1;    PDK4;   

DOI  :  10.1186/s13046-023-02732-y

 received in 2023-03-28, accepted in 2023-06-08,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGlycolysis is the key hallmark of cancer and maintains malignant tumor initiation and progression. The role of N6-methyladenosine (m6A) modification in glycolysis is largely unknown. This study explored the biological function of m6A methyltransferase METTL16 in glycolytic metabolism and revealed a new mechanism for the progression of Colorectal cancer (CRC).MethodsThe expression and prognostic value of METTL16 was evaluated using bioinformatics and immunohistochemistry (IHC) assays. The biological functions of METTL16 in CRC progression was analyzed in vivo and in vitro. Glycolytic metabolism assays were used to verify the biological function of METTL16 and Suppressor of glucose by autophagy (SOGA1). The protein/RNA stability, RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull-down assays were used to explore the potential molecular mechanisms.ResultsSOGA1 is a direct downstream target of METTL16 and involved in METTL16 mediated glycolysis and CRC progression. METTL16 significantly enhances SOGA1 expression and mRNA stability via binding the “reader” protein insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Subsequently, SOGA1 promotes AMP-activated protein kinase (AMPK) complex ubiquitination, inhibits its expression and phosphorylation, thus upregulates pyruvate dehydrogenase kinase 4 (PDK4), a crucial protein controlling glucose metabolism. Moreover, Yin Yang 1 (YY1) can transcriptionally inhibit the expression of METTL16 in CRC cells by directly binding to its promoter. Clinical data showed that METTL16 expression is positively correlated to SOGA1 and PDK4, and is associated with poor prognosis of CRC patients.ConclusionsOur findings suggest that METTL16/SOGA1/PDK4 axis might be promising therapeutic targets for CRC.

【 授权许可】

CC BY   
© The Author(s) 2023

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