Tumor suppressive function of p21-activated kinase 6 in hepatocellular carcinoma [Gene Regulation]

October 6th, 2015 by Liu, W., Liu, Y., Liu, H., Zhang, W., Fu, Q., Xu, J., Gu, J.

Our previous studies identified the oncogenic role of p21-activated kinase 1 (PAK1) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Contrarily, PAK6 was found to predict favorable prognosis in RCC patients. Nevertheless, the ambiguous tumor suppressive function of PAK6 in hepatocarcinogenesis remains obscure. Herein, decreased PAK6 expression was found to be associated with Tumor Node Metastasis (TNM) stage progression and unfavorable overall survival (OS) in HCC patients. Additionally, overexpression and silence of PAK6 experiments showed that PAK6 inhibited xenografted tumor growth in vivo, and restricted cell proliferation, colony formation, migration and invasion and promoted cell apoptosis and anoikis in vitro. Moreover, overexpression of kinase dead and nuclear localization signal (NLS) deletion mutants of PAK6 experiments indicated tumor suppressive function of PAK6 was dependent on its kinase activity and nuclear translocation partially. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components including EZH2, SUZ12 and EED elucidated that epigenetic control of H3K27me3 arbitrated PAK6 downregulation in hepatoma cells. More importantly, negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis.