title: RASSF6 promotes p21(Cip1/Waf1)-dependent cell cycle arrest and apoptosis through activation of the JNK/SAPK pathway in clear cell renal cell carcinoma.
abstract: Clear cell renal cell carcinoma (ccRCC) is a highly aggressive and common pathological subtype of renal cancer. This cancer is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, which leads to the accumulation of hypoxia-inducible factors (HIFs). Although therapies targeted at HIFs can significantly improve survival, nearly all patients with advanced ccRCC eventually succumb to the disease. Thus, additional oncogenic events are thought to be involved in the development of ccRCC tumors. In this study, we investigated the role of RASSF6 in ccRCC. Downregulation of RASSF6 was commonly observed in primary tumors relative to matched adjacent normal tissues. Moreover, functional studies established that ectopic re-expression of RASSF6 in ccRCC cells inhibited cell proliferation, clonogenicity, and tumor growth in mice, whereas silencing of RASSF6 dramatically enhanced cell proliferation in vitro and in vivo. Mechanistic investigation suggested that RASSF6 triggers p21(Cip1/Waf1) accumulation to induce G 1 cell cycle arrest and promote apoptosis upon exposure to pro-apoptotic agents, and both of these mechanisms appear to be mediated by activated JNK signaling. Together, these findings suggest that RASSF6 may play a tumor suppressor role in the progression of ccRCC.
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Yuan-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Li-Xia
authors.initials: LX
authors.lastname: Peng
authors.affiliation: Department of Pathology; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Bi-Jun
authors.initials: BJ
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Sun Yat-sen University Cancer Center; Guangzhou, China.
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Qian
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C519911:RASSF6 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: JNK signaling; RASSF6; apoptosis; ccRCC; cell cycle; p21Cip1/Waf1