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

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 initiation and metastasis by coordinately activating Ras and NF-κB. Specifically, we show that loss of the RasGAP gene DAB2IP induces metastatic prostate cancer in a murine model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-κB through distinct domains to promote tumor initiation and metastasis, respectively. DAB2IP is suppressed in human prostate cancer where 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 EZH2 activates Ras, 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.

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…10,11 The GAP domain of DAB2IP is homologous to other RasGAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines (Figure 2). [12][13][14][15] In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation. 1 Through this activity, DAB2IP can also dampen Ras-induced activation of PI3K, contributing to inhibition of the PI3K-AKT signaling axis.…”

“…This model is well characterized in endothelial cells, but is conserved in other cell types, including cancer cells. 15,18 In TNF-treated cells, DAB2IP can likewise support ASK1-JNK activation by the pro-apoptotic kinase Homeodomain-interacting protein kinase 1 (HIPK1). 19 Notably, DAB2IP also mediates ASK1-JNK activation upon endoplasmic reticulum (ER) stress (Figure 4a).…”

“…Augmented cell proliferation has been correlated to abrogation of DAB2IP functions in various cultured cell lines and in vivo models, and has been linked to loss of Ras-GAP activity and hyperactivation of AKT. 12,15,25 Mice injected with PCa cells overexpressing H-Ras, or depleted for DAB2IP, developed highly proliferative tumors with similar kinetics and maximum size. 15 In this model, wild-type DAB2IP significantly blocked tumor development, whereas expression of a catalytically inactive GAP mutant (DAB2IP-R289L) was ineffective.…”

“…12,15,25 Mice injected with PCa cells overexpressing H-Ras, or depleted for DAB2IP, developed highly proliferative tumors with similar kinetics and maximum size. 15 In this model, wild-type DAB2IP significantly blocked tumor development, whereas expression of a catalytically inactive GAP mutant (DAB2IP-R289L) was ineffective. 15 Tumors formed by DAB2IP-depleted PCa cells also display PI3K-AKT pathway activation.…”

RREB1 Transcription Factor Splice Variants in Urologic Cancer

“…[1][2][3][4][5][6][7] We recently found that the Ral (Ras-like) GTPase pathway downstream of Ras plays an important role in bladder cancer cell migration. 8,9 Notably, the RREB1 (Rasresponsive element binding protein 1) transcription factor was identified as a putative Ral-regulated gene through batch analysis of promoter sequences in Ral target genes.…”