ZDHHC5-mediated BRAF palmitoylation activates the MAPK pathway and drives cholangiocarcinoma progression.

Cholangiocarcinoma is a highly malignant tumor with an increasing incidence around the world. Discovery of novel molecular targets and effective therapies for cholangiocarcinoma are urgently needed. Palmitoylation is a reversible lipid modification mainly catalyzed by ZDHHC family palmitoyltransferases. However, its function and underlying mechanisms in cholangiocarcinoma remain poorly understood. Here, we found that protein palmitoylation levels and ZDHHC5 expression were upregulated in cholangiocarcinoma. Knockdown of ZDHHC5 inhibited the growth of cholangiocarcinoma. Mechanistically, ZDHHC5 modulates the activity of MAPK signaling pathway by regulating palmitoylation of BRAF at Cys194/195. Palmitoylation facilitates the membrane localization of BRAF and stabilizes BRAF protein. Either knockdown of ZDHHC5 or disruption of palmitoylation sites of BRAF inhibited ERK signaling. Furthermore, we found that cholangiocarcinoma cells expressing high levels of ZDHHC5 exhibited increased activities of MAPK signaling pathway and increased sensitivities to MAPK signaling pathway inhibitors. This study identifies a previously unknown ZDHHC5-BRAF-ERK axis that promotes the growth of cholangiocarcinoma and represents a potential crucial role in therapeutic.