The Role of Palmitoyltransferase ZDHHC5 in Regulating RAS Function

More than 90% of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, harbor an activating KRAS mutation which consequently alters its downstream signaling pathways. S ‐palmitoylation is a dynamic post‐translational modification that has been implicated in maintaining the altered function of key oncogenes important in cancer progression. S ‐palmitoylation is catalyzed by a large family of 23 zinc finger DHHC‐type (ZDHHC) palmitoyl S‐acyltransferases. Our understanding of how specific ZDHHC enzymes regulate tumor progression remains limited. Analysis of data available in TCGA indicates that high levels of ZDHHC5 correlates with a poor survival in pancreatic cancer patients. Notably, we observed in published proximity‐dependent biotin labeling studies that the palmitoyltransferase ZDHHC5 is consistently identified as a novel Ras interactor. Accordingly, we hypothesize that ZDHHC5 may modulate the function of Ras in cancer cells. We find that genetic disruption of ZDHHC5 causes loss of Ras activity and membrane localization, consequently decreasing the MAPK pathway in pancreatic cancer cell lines. Biochemical characterization of ZDHHC5‐dependent regulation of Ras function in pancreatic cancer will provide more information on how to target it and create a therapeutic window that will help to prevent pancreatic cancer progression.