An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.
An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.
复制标题
作者：
转移是大多数前列腺癌相关死亡的原因；然而，人们对这一过程背后的分子机制知之甚少。在这里，我们发现了一个癌基因-肿瘤抑制因子级联，通过协调激活Ras和NF-κB促进前列腺癌的发生和转移。具体来说，我们表明RasGAP基因DAB2IP的缺失在小鼠模型中诱导转移性前列腺癌。值得注意的是，DAB2IP作为一个信号支架，通过不同的结构域协调调节Ras和NF-κB，分别促进肿瘤的发生和转移。DAB2IP在人类前列腺癌中被抑制，其表达与肿瘤分级呈负相关，并预测预后。此外，我们报道DAB2IP的表观遗传沉默是polycomb-group蛋白EZH2激活Ras， NF-κB并引发转移的关键机制。这些研究确定了转移性前列腺癌中两种主要途径同时激活的机制，并确立了EZH2作为转移的驱动因素。
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.