An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappa B

作者：Min Junxia; Zaslavsky Alexander; Fedele Giuseppe; McLaughlin Sara K; Reczek Elizabeth E; De Raedt Thomas; Guney Isil; Strochlic David E; MacConaill Laura E; Beroukhim Rameen; Bronson Roderick T; Ryeom Sandra; Hahn William C; Loda Massimo; Cichowski Karen^*

来源：Nature Medicine, 2010, 16(3): 286-U82.

DOI：10.1038/nm.2100

Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappa B (NF-kappa B). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappa B through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappa B and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

• 出版日期2010-3
• 单位MIT