Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma

作者全名："Gou, Dongmei; Liu, Rui; Shan, Xiaoqun; Deng, Haijun; Chen, Chang; Xiang, Jin; Liu, Yi; Gao, Qingzhu; Li, Zhi; Huang, Ailong; Wang, Kai; Tang, Ni"

作者地址："[Gou, Dongmei; Liu, Rui; Shan, Xiaoqun; Deng, Haijun; Xiang, Jin; Liu, Yi; Gao, Qingzhu; Huang, Ailong; Wang, Kai; Tang, Ni] Second Affiliated Hosp, Inst Viral Hepatitis, Dept Infect Dis, Key Lab Mol Biol Infect Dis,Minist Educ, Chongqing, Peoples R China; [Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Li, Zhi] Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing, Peoples R China"

通信作者："Huang, AL; Wang, K; Tang, N (通讯作者)，Second Affiliated Hosp, Inst Viral Hepatitis, Dept Infect Dis, Key Lab Mol Biol Infect Dis,Minist Educ, Chongqing, Peoples R China."

来源：JOURNAL OF CLINICAL INVESTIGATION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001034773300001

JCR分区：Q1

影响因子：13.3

年份：2023

卷号：133

期号：13

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency- induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 KO in vivo and in vitro. These findings reveal the availability of the key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC."

基金机构："China National Natural Science Foundation [82273238, U20A20392, 82072286, 82272975]; 111 Project [D20028]; Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau) [2023DBXM007]; Senior Medical Talents Program of Chongqing for Young and Middle-aged; Kuanren talents program of the Second Affiliated Hospital of Chongqing Medical University; Science and Technology Research Program of Chongqing Municipal Education Commission [HZ2021006, KJZDM202000401]; Future Medical Youth Innovation Team of Chongqing Medical University [W0036, W0101]; Talent Development Program of CQMU for Postgraduate [BJRC202115]"

基金资助正文："We are grateful to T.-C. He for providing the pAdEasy system and for critical reading of the manuscript. We thank Ding Xue (Tsin-ghua University, Beijing, China) for supplying the CRISPR/Cas9 system. We thank Bing Sun (Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China) for providing the pLL3.7 vector. We also thank Hui Fan (Chongqing Medical University) for helpful advice and discussion. This work was supported by the China National Natural Science Foundation (grant no. 82273238, U20A20392, 82072286, 82272975), the 111 Project (No. D20028), the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007), Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Kuanren talents program of the Second Affiliated Hospital of Chongqing Medical University, the Science and Technology Research Program of Chongqing Municipal Education Commission (HZ2021006, KJZDM202000401), the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101), and the Talent Development Program of CQMU for Postgraduate (grant BJRC202115)"