中文版 | English
Title

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

Author
Corresponding AuthorZhang, Zhonglin; Yuan, Yufeng
Publication Years
2023-03-01
DOI
Source Title
EISSN
2523-3548
Volume43Issue:3
Abstract
BackgroundHepatocellular 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. MethodsIn 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. ResultsWe 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. ConclusionsThese 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.
Keywords
URL[Source Record]
Indexed By
Language
English
SUSTech Authorship
Others
Funding Project
Cancer Research and Translational Platform Project of Zhongnan Hospital of Wuhan University[WJ2021M255] ; Translational Medicine and Interdisciplinary Research Joint Fund Project of Zhongnan Hospital of Wuhan University[ZLYNXM202004] ; National Key Research and Development Program of China[ZNJC201918] ; Natural Science Foundation of Hubei Province[SQ2019YFC200078/02] ; null[2022CFB184]
WOS Research Area
Oncology
WOS Subject
Oncology
WOS Accession No
WOS:000907632000001
Publisher
Data Source
Web of Science
Citation statistics
Cited Times [WOS]:11
Document TypeJournal Article
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/583158
DepartmentShenzhen People's Hospital
Affiliation
1.Wuhan Univ, Zhongnan Hosp, Dept Hepatobiliary & Pancreat Surg, Wuhan 430062, Hubei, Peoples R China
2.Clin Med Res Ctr Minimally Invas Procedure Hepatob, Wuhan, Hubei, Peoples R China
3.Yangtze Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Jingzhou, Hubei, Peoples R China
4.Southern Univ Sci & Technol, Jinan Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp,Dept Clin & Translat Res Ct, Shenzhen, Guangdong, Peoples R China
5.Clin Med Res Ctr Minimally Invas Procedure Hepatob, Wuhan 430062, Hubei, Peoples R China
Recommended Citation
GB/T 7714
Xia, Peng,Zhang, Hao,Lu, Haofeng,et al. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression[J]. CANCER COMMUNICATIONS,2023,43(3).
APA
Xia, Peng.,Zhang, Hao.,Lu, Haofeng.,Xu, Kequan.,Jiang, Xiang.,...&Yuan, Yufeng.(2023).METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression.CANCER COMMUNICATIONS,43(3).
MLA
Xia, Peng,et al."METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression".CANCER COMMUNICATIONS 43.3(2023).
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