Collaboration of Kras and androgen receptor signaling stimulates EZH2 expression and tumor-propagating cells in prostate cancer.
Collaboration of Kras and androgen receptor signaling stimulates EZH2 expression and tumor-propagating cells in prostate cancer.
复制标题
DOI：
10.1158/0008-5472.can-12-0228
复制
发表时间：
2012-09-15
期刊：
影响因子：
11.2
通讯作者：
Witte ON
中科院分区：
文献类型：
--
作者：
Cai H;Memarzadeh S;Stoyanova T;Beharry Z;Kraft AS;Witte ON
染色质阻遏因子EZH2的升高与包括前列腺癌在内的几种人类癌症的进展和预后不良相关。然而，驱动EZH2表达的机制尚未完全了解。在这项研究中，我们研究了雄激素受体（AR），Kras和Akt激活导致的小鼠前列腺癌的功能协同作用，这些受体驱动前列腺癌中三种最常激活的致癌信号通路。虽然这三个事件中的任何两个都足以促进前列腺癌的形成和进展，但只有AR和Kras信号传导的协同作用才能提高EZH2表达并在体内扩增前列腺癌祖细胞。我们的研究结果揭示了在侵袭性前列腺癌进展过程中导致EZH2表达增强的遗传机制，这对理解如何靶向晚期疾病具有重要意义，其中癌症祖细胞可能至关重要。
Elevation of the chromatin repression factor EZH2 is associated with progression and poor prognosis in several human cancers, including prostate cancer. However, the mechanisms driving EZH2 expression are not fully understood. In this study, we investigated the functional synergy in prostate cancers in mice resulting from activation of the androgen receptor (AR), Kras and Akt, which drive three of the most frequently activated oncogenic signaling pathways in prostate cancer. While any two of these three events were sufficient to promote the formation and progression of prostate cancer, only the synergy of AR and Kras signaling could elevate EZH2 expression and expand prostate cancer progenitor cells in vivo. Our findings have revealed a genetic mechanism resulting in enhanced EZH2 expression during the progression of aggressive prostate cancer, with important implications for understanding how to target advanced disease where cancer progenitor cells may be critical.