ZDHHC20-Mediated S-Palmitoylation of YTHDF3 Stabilizes MYC mRNA to Promote Pancreatic Cancer Progression

Post-translational modifications of malignant transformation and tumor maintenance in pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remains largely unexplored. Here, we used 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 lysosomal localization and 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 designed a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulated MYC expression and inhibited 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.