Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase(G6PD)by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis

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外文摘要：Betaine-homocysteine methyltransferase(BHMT)regulates protein methylation and is correlated with tumorigenesis;however,the effects and regulation of BHMT in hepatocarcinogenesis remain largely unexplored.Here,we determined the clinical significance of BHMT in the occurrence and progression of hepatocellular carcinoma(HCC)using tissue samples from 198 patients.BHMT was to be frequently found(86.6％)expressed at relatively low levels in HCC tissues and was positively correlated with the overall survival of patients with HCC.Bhmt overexpression effectively suppressed several malignant phenotypes in hepatoma cells in vitro and in vivo,whereas complete knockout of Bhmt(Bhmt-/-)produced the opposite effect.We combined proteomics,metabolomics,and molecular biological strategies and detected that Bhmt-/-promoted hepatocarcinogenesis and tumor progression by enhancing the activity of glucose-6-phosphate dehydrogenase(G6PD)and PPP metabolism in DEN-induced HCC mouse and subcutaneous tumor-bearing models.In contrast,restoration of Bhmt with an AAV8-Bhmt injection or pharmacological inhibition of G6PD attenuated hepatocarcinogenesis.Additionally,coimmunoprecipitation identified monomethylated modifications of the G6PD,and BHMT regulated the methylation of G6PD.Protein sequence analysis,generation and application of specific antibodies,and site-directed mutagenesis indicated G6PD methylation at the arginine residue 246.Furthermore,we established bidirectionally regulated BHMT cellular models combined with methylation-deficient G6PD mutants to demonstrate that BHMT potentiated arginine methylation of G6PD,thereby inhibiting G6PD activity,which in turn suppressed hepatocarcinogenesis.Taken to-gether,this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency,suggesting a potential therapeutic strategy for HCC treatment.

外文关键词：

HCCBHMTarginine methylationG6PDPPP metabolism

作者：

Jie Gao、Xiaoyi Shi、Yaohui Sun、Xudong Liu、Feng Zhang、Chengcheng Shi、Xiao Yu、Zhiping Yan、Long Liu、Shizhe Yu、Jiacheng Zhang、Xiaodan Zhang、Shuijun Zhang、Wenzhi Guo

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作者单位：

Department of Hepatobiliary and Pancreatic Surgery,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China

Henan Diagnosis & Treatment League for Hepatopathy,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China

Henan Innovative Research Group for Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation,Zhengzhou 450052,China

Henan Organ Transplantation Quality Control Centre,Zhengzhou 450052,China

Henan Engineering Technology Research Center for Org

Henan Engineering Technology Research Center for Organ Transplantation,Zhengzhou 450052,China

Department of Pharmacy,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China

Department of General Surgery,Huashan Hospital,Fudan University Shanghai 200040,China

Cancer Metastasis Institute,Fudan University,Shanghai 200040,China

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基金：

National Natural Science Foundation of ChinaHigher Education Disciplinary Innovation ProgramHenan Province Medical Science and Technology Research PlanHenan Province Medical Science and Technology Research Plan"Science and Technology to create Central Plains"Young Talent Lifting ProjectHenan Charity General Federation of Hepatobiliary Care Fund

项目编号：

82103282D20036SBGJ202103061LHGJ201901352023HYTP041GDXZ2023002

出版年：

2024

DOI：

10.1007/s11427-023-2481-3

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(8)

参考文献量2