title: Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma.
abstract: 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 a 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 stage progression and unfavorable overall survival 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 deletion mutants of PAK6 experiments indicated the tumor suppressive function of PAK6 was partially dependent on its kinase activity and nuclear translocation. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components, including EZH2, SUZ12, and EED, elucidated epigenetic control of H3K27me3-arbitrated PAK6 down-regulation 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.
authors.affiliation: Departments of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032.
authors.forename: Weisi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China.
authors.forename: Haiou
authors.initials: H
authors.lastname: Liu
authors.affiliation: Departments of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Departments of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Departments of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032. Electronic address: jjxufdu@fudan.edu.cn.
authors.forename: Jiejie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Departments of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D016147:Genes, Tumor Suppressor; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D015996:Survival Rate; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C429007:PAK6 protein, human; D054462:p21-Activated Kinases
keywords: cancer biology; enhancer of zeste homolog 2; hepatocellular carcinoma; histone methylation; overall survival; polycomb; prognostic factor; serine/threonine-protein kinase PAK 6 (PAK6)