ZNF191 inhibits intrahepatic cholangiocarcinoma cell motility and metastasis through SAC1-mediated Cdc42 inactivation.

Metastasis remains the primary cause of intrahepatic cholangiocarcinoma (ICC)-associated mortality. However, the underlying mechanism of ICC metastasis and how it is involved in cell motility remains largely unknown. In the present study, we showed that zinc finger transcription factor 191 (ZNF191) expression levels negatively correlated with metastasis and poor survival of patients with ICC. ZNF191 depletion promoted ICC cell migration, invasion, and motility in vitro, as well as metastases in vivo. Mechanistically, ZNF191 positively regulated mRNA and protein expression of phosphatidylinositol-3-phosphatase SAC1, a negative regulator of tumor metastasis. ZNF191 activated the SAC1 promoter and directly bound to the promoter at nt-1038 (ATTAATT). ZNF191 inhibited actin cytoskeletal assembly including focal adhesion and filopodia formation, as well as Rho GTPases cell division cycle 42 (Cdc42) activation, whereas SAC1 mediated the process. Moreover, SAC1 expression correlated positively with ZNF191 in human ICCs. ZCL278, a specific inhibitor of Cdc42, significantly blocked the effects of ZNF191 on ICC cell motility, migration, and invasion in vitro, as well as metastases in vivo. Thus, ZNF191 directly upregulates SAC1 transcription, then inhibits Cdc42 activation and actin cytoskeletal assembly in ICC cells, eventually inhibiting metastasis. Collectively, ZNF191 may serve as a new prognostic biomarker and potential therapeutic target for ICC metastasis.