METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression

Cancer Communications

article

Peng Xia¹  Hao Zhang¹  Haofeng Lu¹  Kequan Xu¹  Xiang Jiang¹  Yuke Jiang⁴  Xiangdong Gongye¹  Zhang Chen¹  Jie Liu¹  Xi Chen¹  Weijie Ma¹  Zhonglin Zhang¹  Yufeng Yuan¹ 

[1] Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University;Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Yangtze University;Department of Clinical and Translational Research Center, Shenzhen People's Hospital ,(The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)

关键词: METTL5;    c-Myc;    USP5;    P300;    CREB1;    deubiquitination;    hepatocellular carcinoma;    glucose metabolism;   

DOI  :  10.1002/cac2.12403

学科分类：社会科学、人文和艺术（综合）

来源: Springer

【 摘 要 】

Background Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in the world, with a high likelihood of metastasis and a dismal prognosis. The reprogramming of glucose metabolism is critical in the development of HCC. The Warburg effect has recently been confirmed to occur in a variety of cancers, including HCC. However, little is known about the molecular biological mechanisms underlying the Warburg effect in HCC cells. In this study, we sought to better understand how methyltransferase 5, N6-adenosine (METTL5) controls the development of HCC and the Warburg effect.Methods In the current study, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of METTL5 in HCC tissues and cell lines. Several different cell models and animal models were established to determine the role of METTL5 in glucose metabolism reprogramming and the underlying molecular mechanism of HCC. Glutathione-S-transferase pulldown, coimmunoprecipitation, RNA sequencing, non-targeted metabolomics, polysome profiling, and luciferase reporter assays were performed to investigate the molecular mechanisms of METTL5 in HCC cells.Results We discovered that METTL5 drove glucose metabolic reprogramming to promote the proliferation and metastasis of HCC. Mechanistically, upregulation of METTL5 promoted c-Myc stability and thus activated its downstream glycolytic genes lactate dehydrogenase A (LDHA), enolase 1 (ENO1), triosephosphate isomerase 1 (TPI1), solute carrier family 2 member 1 (SLC2A1), and pyruvate kinase M2 (PKM2). The c-Box and ubiquitin binding domain (UBA) regions of ubiquitin specific peptidase 5 (USP5) binded to c-Myc protein and inhibited K48-linked polyubiquitination of c-Myc. Further study revealed that METTL5 controled the USP5 translation process, which in turn regulated the ubiquitination of c-Myc. Furthermore, we identified cAMP responsive element binding protein 1 (CREB1)/P300 as a critical transcriptional regulator of METTL5 that promoted the transcription of METTL5 in HCC. In patient-derived tumor xenograft (PDX) models, adenovirus-mediated knockout of METTL5 had a good antitumor effect and prolonged the survival of PDX-bearing mice.Conclusions These findings point to a novel mechanism by which CREB1/P300-METTL5-USP5-c-Myc controls abnormal glucose metabolism and promotes tumor growth, suggesting that METTL5 is a potential therapeutic target and prognostic biomarker for HCC.

【 授权许可】

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