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

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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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Acknowledgement

This work was supported by the National Natural Science Foundation of China (82103282), Higher Education Disciplinary Innovation Program (D20036), Henan Province Medical Science and Technology Research Plan (SBGJ202103061, LHGJ20190135), “Science and Technology to create Central Plains” Young Talent Lifting Project (2023HYTP041), and Henan Charity General Federation of Hepatobiliary Care Fund (GDXZ2023002).

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Authors and Affiliations

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

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

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

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

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

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

  4. Henan Organ Transplantation Quality Control Centre, Zhengzhou, 450052, China

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

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

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

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

    Chengcheng Shi

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

    Shizhe Yu

  8. Cancer Metastasis Institute, Fudan University, Shanghai, 200040, China

    Shizhe Yu

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  1. Jie Gao
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Gao, J., Shi, X., Sun, Y. et al. Deficiency of betaine-homocysteine methyltransferase activates glucose-6-phosphate dehydrogenase (G6PD) by decreasing arginine methylation of G6PD in hepatocellular carcinogenesis. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2481-3

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