Signaling metabolite succinylacetone activates HIF-1α and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma

作者全名："Luo, Huating; Wang, Qiujie; Yang, Fan; Liu, Rui; Gao, Qingzhu; Cheng, Bin; Lin, Xue; Huang, Luyi; Chen, Chang; Xiang, Jin; Wang, Kai; Qin, Bo; Tang, Ni"

作者地址："[Luo, Huating; Wang, Qiujie; Gao, Qingzhu; Cheng, Bin; Lin, Xue; Huang, Luyi; Xiang, Jin; Tang, Ni] Chongqing Med Univ, Inst Viral Hepatitis, Affiliated Hosp 2, Key Lab Mol Biol Infect Dis,Minist Educ,Dept Infec, Chongqing, Peoples R China; [Luo, Huating] Chongqing Med Univ, Affiliated Hosp 1, Dept Geriatr, Chongqing, Peoples R China; [Yang, Fan; Qin, Bo] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing, Peoples R China; [Liu, Rui] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastrointestinal Surg, Chongqing, Peoples R China; [Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Wang, Kai; Tang, Ni] Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China; [Qin, Bo] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing 400016, Peoples R China"

通信作者："Wang, K; Tang, N (通讯作者)，Chongqing Med Univ, Inst Viral Hepatitis, Key Lab Mol Biol Infect Dis, Dept Infect Dis,Affiliated Hosp 2,Minist Educ, Chongqing 400010, Peoples R China.; Qin, B (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing 400016, Peoples R China."

来源：JCI INSIGHT

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001122686100001

JCR分区：Q1

影响因子：6.3

年份：2023

卷号：8

期号：23

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1 alpha stability and activating the HIF-1 alpha signaling pathway. However, whether other metabolites regulate HIF-1 alpha stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine/tyrosine catabolism, glutathione S-transferase zeta 1 (GSTZ1), led to accumulation of succinylacetone, which was structurally similar to alpha-ketoglutarate. Succinylacetone competed with alpha-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1 alpha, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1 alpha/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1 alpha inhibitor combined with anti- programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment."

基金机构："National Natural Science Foundation of China [82272975, 82273238, 82203796]; 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 Innovative and Entrepreneurial Team of Chongqing Talents Plan; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0036, W0101]; Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University, Chongqing Natural Science Foundation Committee [cstc2020jcyj-msxmX0982]; First Affiliated Hospital of Chongqing Medical University, Scientific Research and Cultivation Fund Project [PyJJ2020-01]; Talent Development Program of Chongqing Medical University for Postgraduate [BJRC202220]"

基金资助正文："We would like to thank TC He (University of Chicago, Chicago, Illinois, USA) for providing the AdEasy system. We are grateful to Ding Xue (Tsinghua University, Beijing, China) for supplying the CRISPR/Cas9 system. This study was supported by the National Natural Science Foundation of China (Grant 82272975, to NT; 82273238, to KW; 82203796, to QG) , Chongqing Medical Scientific Research Project (Joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007, to NT) , Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0036, to NT; W0101, to KW) , Kuanren Talents Program of The Second Affiliated Hospital of Chongqing Medical University, Chongqing Natural Science Foundation Committee, General Program (cstc2020jcyj-msxmX0982, to FY) , The First Affiliated Hospital of Chongqing Medical University, Scientific Research and Cultivation Fund Project (PyJJ2020-01, to FY) , and the Talent Development Program of Chongqing Medical University for Postgraduate (grant BJRC202220, to QW) ."