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

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          Abstract

          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-kappaB (NF-kappaB). 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-kappaB 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-kappaB 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.

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          Author and article information

          Journal
          Nat Med
          Nature medicine
          Springer Science and Business Media LLC
          1546-170X
          1078-8956
          Mar 2010
          : 16
          : 3
          Affiliations
          [1 ] Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
          Article
          nm.2100 NIHMS211415
          10.1038/nm.2100
          2903662
          20154697
          6459e629-e74e-4414-b6b2-f9c5ccb0e8cf
          History

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