2. Academic Validation
  3. ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis

ZDHHC20 mediated S-palmitoylation of fatty acid synthase (FASN) promotes hepatocarcinogenesis

  • Mol Cancer. 2024 Dec 19;23(1):274. doi: 10.1186/s12943-024-02195-5.
Yaqi Mo # 1,  Yamei Han # 2,  Yang Chen 2 3,  Chunling Fu 4,  Qing Li 1,  Zhuang Liu 2,  Mingming Xiao 5 6,  Bo Xu 7 8
Affiliations

Affiliations

  • 1 Center for Intelligent Oncology, Chongqing University Cancer Hospital and Chongqing University School of Medicine, and Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing, 400030, China.
  • 2 Department of Biochemistry and Molecular Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
  • 3 Department of Radiation Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
  • 4 Department of Pathology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
  • 5 Department of Biochemistry and Molecular Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. xiaomingming@fudanpci.org.
  • 6 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. xiaomingming@fudanpci.org.
  • 7 Center for Intelligent Oncology, Chongqing University Cancer Hospital and Chongqing University School of Medicine, and Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing, 400030, China. xubo731@cqu.edu.cn.
  • 8 Department of Biochemistry and Molecular Biology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China. xubo731@cqu.edu.cn.
  • # Contributed equally.
PMID: 39696259 DOI: 10.1186/s12943-024-02195-5
Abstract

Background: Protein palmitoylation is a reversible fatty acyl modification that undertakes important functions in multiple physiological processes. Dysregulated palmitoylations are frequently associated with the formation of Cancer. How palmitoyltransferases for S-palmitoylation are involved in the occurrence and development of hepatocellular carcinoma (HCC) is largely unknown.

Methods: Chemical carcinogen diethylnitrosamine (DEN)-induced and DEN combined CCl4 HCC models were used in the zinc finger DHHC-type palmitoyltransferase 20 (ZDHHC20) knockout mice to investigate the role of ZDHHC20 in HCC tumourigenesis. Palmitoylation liquid chromatography-mass spectrometry analysis, acyl-biotin exchange assay, co-immunoprecipitation, ubiquitination assays, protein half-life assays and immunofluorescence microscopy were conducted to explore the downstream regulators and corresponding mechanisms of ZDHHC20 in HCC.

Results: Knocking out of ZDHHC20 significantly reduced hepatocarcinogenesis induced by chemical agents in the two HCC mouse models in vivo. 97 proteins with 123 cysteine sites were found to be palmitoylated in a ZDHHC20-dependent manner. Among these, fatty acid synthase (FASN) was palmitoylated at cysteines 1471 and 1881 by ZDHHC20. The genetic knockout or pharmacological inhibition of ZDHHC20, as well as the mutation of the critical cysteine sites of FASN (C1471S/C1881S) accelerated the degradation of FASN. Furthermore, ZDHHC20-mediated FASN palmitoylation competed against the ubiquitin-proteasome pathway via the E3 ubiquitin Ligase complex SNX8-TRIM28.

Conclusions: Our findings demonstrate the critical role of ZDHHC20 in promoting hepatocarcinogenesis, and a mechanism underlying a mutual restricting mode for protein palmitoylation and ubiquitination modifications.

Keywords

FASN; Hepatocarcinogenesis; S-palmitoylation; ZDHHC20.

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