ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression

Huan Zhang, Yan Sun, Zhaokai Wang, Xiaoju Huang, Lu Tang (), Ke Jiang () and Xin Jin ()
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Huan Zhang: Huazhong University of Science and Technology
Yan Sun: Huazhong University of Science and Technology
Zhaokai Wang: Huazhong University of Science and Technology
Xiaoju Huang: Huazhong University of Science and Technology
Lu Tang: Huazhong University of Science and Technology
Ke Jiang: Huazhong University of Science and Technology
Xin Jin: Central South University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20–YTHDF3–MYC signaling axis in pancreatic cancer.

Date: 2024
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DOI: 10.1038/s41467-024-49105-3

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