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Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.
Lao, Yuanxiang; Cui, Xiaohan; Xu, Zhu; Yan, Hongyao; Zhang, Zechuan; Zhang, Zhenwei; Geng, Longpo; Li, Binghua; Lu, Yijun; Guan, Qifei; Pu, Xiaohong; Zhao, Suwen; Zhu, Jiapeng; Qin, Xihu; Sun, Beicheng.
Afiliação
  • Lao Y; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Cui X; Department of Gastrointestinal Surgery, General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • Xu Z; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Yan H; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Zhang Z; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Zhang Z; Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China.
  • Geng L; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Li B; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Lu Y; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Guan Q; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
  • Pu X; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical
  • Zhao S; The iHuman Institute, Shanghai Tech University, Shanghai, China.
  • Zhu J; School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Jiangsu, China.
  • Qin X; Department of Hepato-biliary-pancreatic Surgery, the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Jiangsu, China.
  • Sun B; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University & Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui pr
J Hepatol ; 2024 May 31.
Article em En | MEDLINE | ID: mdl-38825017
ABSTRACT
BACKGROUND &

AIMS:

Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression.

METHODS:

Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- as well as Ctnnboe; METoe- driven mouse models were adopted to validate GCDH effects on HCC suppression.

RESULTS:

GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy.

CONCLUSION:

GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDHlow population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDHlow population. IMPACT AND IMPLICATIONS GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article