Targeting the ZDHHC9-mediated STAT1 palmitoylation-phosphorylation conversion inhibits gastric cancer progression.

[BACKGROUND] Palmitoyl transferases ZDHHCs and its mediated protein palmitoylation in several malignant tumors have been reported. However, the role in gastric cancer (GC) has not yet been fully elucidated.

[METHODS] Various experimental techniques were employed to investigate the role of ZDHHCs and related protein palmitoylation in GC, mainly including acyl-biotinyl exchange assay, co-immunoprecipitation, immunohistochemistry, western blot, immunofluorescence, and confocal imaging.

[RESULTS] We identified widespread protein palmitoylation in GC, and the palmitoylation inhibitor 2-bromopalmitate was found to inhibit progression of GC in vitro. Screening of differentially expressed ZDHHCs revealed that abnormal overexpression of ZDHHC9 was associated with poor prognosis in GC patients. Silencing ZDHHC9 inhibited GC growth and induced apoptosis. Further, ZDHHC9 palmitoylated STAT1 at Cys577. More specifically, ZDHHC9 mediated STAT1 conversion of Cys577 S-palmitoylation and Tyr701 phosphorylation via the JAK1-STAT1 signaling pathway. Notably, palmitoylation of STAT1 at Cys577 is a key mediator of ZDHHC9-mediated GC progression, relying on nuclear pSTAT1-Tyr701 and its transcription of downstream genes.

[CONCLUSIONS] Taken together, ZDHHC9 promotes GC progression by regulating the conversion of STAT1 S-palmitoylation and phosphorylation, providing potential therapeutic targets for GC treatment.