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Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase (G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis.
Gao, Jie; Shi, Xiaoyi; Sun, Yaohui; Liu, Xudong; Zhang, Feng; Shi, Chengcheng; Yu, Xiao; Yan, Zhiping; Liu, Long; Yu, Shizhe; Zhang, Jiacheng; Zhang, Xiaodan; Zhang, Shuijun; Guo, Wenzhi.
Affiliation
  • Gao J; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Shi X; Henan Diagnosis & Treatment League for Hepatopathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Sun Y; Henan Innovative Research Group for Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation, Zhengzhou, 450052, China.
  • Liu X; Henan Organ Transplantation Quality Control Centre, Zhengzhou, 450052, China.
  • Zhang F; Henan Engineering Technology Research Center for Organ Transplantation, Zhengzhou, 450052, China.
  • Shi C; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Yu X; Henan Diagnosis & Treatment League for Hepatopathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Yan Z; Henan Innovative Research Group for Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation, Zhengzhou, 450052, China.
  • Liu L; Henan Organ Transplantation Quality Control Centre, Zhengzhou, 450052, China.
  • Yu S; Henan Engineering Technology Research Center for Organ Transplantation, Zhengzhou, 450052, China.
  • Zhang J; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Zhang X; Henan Diagnosis & Treatment League for Hepatopathy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Zhang S; Henan Innovative Research Group for Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation, Zhengzhou, 450052, China.
  • Guo W; Henan Organ Transplantation Quality Control Centre, Zhengzhou, 450052, China.
Sci China Life Sci ; 67(8): 1648-1665, 2024 Aug.
Article in En | MEDLINE | ID: mdl-38679670
ABSTRACT
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 together, this study reveals a new methylation-regulatory mechanism in hepatocarcinogenesis owing to BHMT deficiency, suggesting a potential therapeutic strategy for HCC treatment.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Betaine-Homocysteine S-Methyltransferase / Carcinogenesis / Glucosephosphate Dehydrogenase / Liver Neoplasms Limits: Animals / Humans / Male Language: En Journal: Sci China Life Sci Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Hepatocellular / Betaine-Homocysteine S-Methyltransferase / Carcinogenesis / Glucosephosphate Dehydrogenase / Liver Neoplasms Limits: Animals / Humans / Male Language: En Journal: Sci China Life Sci Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Country of publication: