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-κB (NF-κB). 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-κB 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-κB 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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21 February 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41591-024-02866-2
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Acknowledgements
The PMMP-luc-neo retroviral luciferase construct was generously provided by A.L. Kung and M. Chheda (Dana-Farber Cancer Institute (DFCI)). pRL-TK was a gift from J. Boehm (Broad Institute). We thank D. Barbie (DFCI), J. Boehm for NF-κB target primers and R. Chen (DFCI) for IκBαSR and G. Evan for helpful discussions. This grant was supported by in part by the US Department of Defense (PC074048) and the Ludwig Center at Dana-Farber/Harvard Cancer Center.
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J.M., A.Z., S.K.M., E.E.R., I.G. and D.E.S. performed in vitro and in vivo experiments. G.F., R.T.B. and M.L. analyzed and interpreted the immunohistochemistry and histology experiments. G.F. performed analysis on tissue microarrays. T.D.R. performed statistical analysis. L.E.M. and R.B. performed Sequenome analysis. S.R., W.C.H. and M.L. provided scientific advice and helpful comments on manuscript. J.M. and K.C. conceptualized experiments, prepared figures and drafted the manuscript.
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Min, J., Zaslavsky, A., Fedele, G. et al. An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat Med 16, 286–294 (2010). https://doi.org/10.1038/nm.2100
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DOI: https://doi.org/10.1038/nm.2100
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