ZDHHC9-mediated CD38 palmitoylation stabilizes CD38 expression and promotes pancreatic cancer growth.

The cluster of differentiation 38 (CD38) is a multifunctional transmembrane protein involved in numerous physiological and pathological processes including aging, neurodegenerative diseases, and tumorigenesis, hence is an attractive drug target. However, the mechanisms underlying the regulation of CD38 expression remain enigmatic. Herein, we report for the first time that CD38 is palmitoylated at Cys16, and that S-palmitoylation is required to maintain CD38 protein expression in tumor cells. Furthermore, we identify DHHC9 as the palmitoyl transferase and APT1 as the acylprotein thioesterase responsible for this crucial post-translational modification. Finally, we designed a competitive peptide of CD38 palmitoylation that decreases CD38 expression in tumor cells and suppresses tumor progression in vivo. These findings provide novel insight into CD38 regulation and highlight potential therapeutic strategies targeting CD38 palmitoylation for cancer treatment.