ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma

Mingzhi Wu; Xiaojun Zhou; Xinyi Zhou; Genxin Wang; Yiqun Zeng; Jun Li; Edward V Prochownik; Fubing Wang; Youjun Li

doi:10.1016/j.celrep.2024.114962

ZDHHC3-mediated SCAP S-acylation promotes cholesterol biosynthesis and tumor immune escape in hepatocellular carcinoma

Cell Rep. 2024 Nov 9;43(11):114962. doi: 10.1016/j.celrep.2024.114962. Online ahead of print.

Authors

Mingzhi Wu¹, Xiaojun Zhou¹, Xinyi Zhou¹, Genxin Wang¹, Yiqun Zeng¹, Jun Li¹, Edward V Prochownik², Fubing Wang³, Youjun Li⁴

Affiliations

¹ Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
² Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Department of Microbiology and Molecular Genetics, Pittsburgh Liver Research Center and Hillman Cancer Center of UPMC, Pittsburgh, PA 15224, USA.
³ Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China. Electronic address: wangfubing@znhospital.cn.
⁴ Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: liy7@whu.edu.cn.

PMID: 39522165
DOI: 10.1016/j.celrep.2024.114962

Abstract

Cholesterol metabolism reprogramming plays essential roles in hepatocellular carcinoma (HCC). However, precisely how cholesterol metabolism is dysregulated is not clear. Here, we show that the palmitoyltransferase ZDHHC3 and depalmitoylase ABHD17A regulate HCC cell cholesterol biosynthesis by dynamically S-acylating SREBP cleavage-activating protein (SCAP). SCAP S-acylation by ZDHHC3 at C264 antagonizes HACE1-mediated SCAP ubiquitination. Intriguingly, SREBP2 transcriptionally upregulates ZDHHC3 to form a positive feedback loop, which explains why negative feedback regulation of SCAP/SREBP2 signaling fails in HCC. Increased cholesterol in the tumor microenvironment (TME) restrains CD4⁺ T cell cytotoxicity. Hence, the cholesterol metabolism reprogramming and cholesterol level alternation in the TME cooperate to promote HCC development. We identified a small-molecule inhibitor of ZDHHC3 that, combined with anti-PD-1 immunotherapy, inhibited diethyl nitrosamine (DEN)/CCl₄-induced HCC growth in mice. ZDHHC3-mediated SCAP S-acylation reprograms cholesterol metabolism and promotes HCC immune escape. ZDHHC3 is thus identified as a rational chemotherapy target for HCC.

Keywords: CP: Cancer; CP: Metabolism; HCC; SCAP/SREBP2; ZDHHC3; cholesterol metabolism; palmitoylation; ubiquitination.