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.
Min
Junxia
J
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Zaslavsky
Alexander
A
Fedele
Giuseppe
G
McLaughlin
Sara K
SK
Reczek
Elizabeth E
EE
De Raedt
Thomas
T
Guney
Isil
I
Strochlic
David E
DE
Macconaill
Laura E
LE
Beroukhim
Rameen
R
Bronson
Roderick T
RT
Ryeom
Sandra
S
Hahn
William C
WC
Loda
Massimo
M
Cichowski
Karen
K
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