ARHGAP21 enhances metastasis in hepatocellular carcinoma by inhibiting ubiquitination of filamin A.

Rho GTPase-activating protein 21 (ARHGAP21) plays a role in the occurrence and development of certain cancers, but its function in hepatocellular carcinoma (HCC) remains unclear. In this study, elevated ARHGAP21 expression was observed in both HCC cell lines and tissues and correlated with poor patient prognosis. Knockdown of ARHGAP21 suppressed HCC cell migration and invasion in vitro by regulating the actin cytoskeleton, while overexpression of ARHGAP21 had the opposite effect. In vivo, knockdown of ARHGAP21 inhibited HCC tumorigenesis and metastasis. Mechanistically, we demonstrated that ARHGAP21 directly binds to FLNA, and the PDZ domain of ARHGAP21 functions as a potential mediator of its binding to the 1-1200 aa fragment of FLNA. ARHGAP21 also directly binds to and recruits HSP90α to stabilize FLNA by inhibiting its ubiquitination and degradation. Overexpression of FLNA reversed the cytoskeleton remodeling-related suppression of tumor metastasis in ARHGAP21-knockdown HCC cells. These results revealed that ARHGAP21 promotes cytoskeleton remodeling and stimulates HCC metastasis by inhibiting FLNA ubiquitination and degradation via HSP90α recruitment. Our results position ARHGAP21 as both a potential prognostic marker and a promising therapeutic target in HCC.