Author:
Wei Wei,Zhang Zhong-Yuan,Shi Bin,Cai Yike,Zhang Hou-Shun,Sun Chun-Lei,Fei Yun-Fei,Zhong Wen,Zhang Shuang,Wang Chen,He Bing,Jiang Guan-Min,Wang Hao
Abstract
Abstract
Background
Glycolysis 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).
Methods
The 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.
Results
SOGA1 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.
Conclusions
Our findings suggest that METTL16/SOGA1/PDK4 axis might be promising therapeutic targets for CRC.
Funder
the Scientific Research Project of Anhui Provincial Education Department
the Natural Science Foundation of Anhui Province
Youth Innovation Project of the University of Science and Technology of China
the National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Cited by
16 articles.
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