An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.
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.
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Junxia
J
Min
Alexander
A
Zaslavsky
Giuseppe
G
Fedele
Sara K
SK
McLaughlin
Elizabeth E
EE
Reczek
Thomas
T
De Raedt
Isil
I
Guney
David E
DE
Strochlic
Laura E
LE
Macconaill
Rameen
R
Beroukhim
Roderick T
RT
Bronson
Sandra
S
Ryeom
William C
WC
Hahn
Massimo
M
Loda
Karen
K
Cichowski
D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009368:Neoplasm Transplantation; D009857:Oncogenes / Q000502:physiology*; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D020703:ras GTPase-Activating Proteins / Q000502:physiology*
C462952:DAB2IP protein, human; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014157:Transcription Factors; D020703:ras GTPase-Activating Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2