MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer.
MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer.
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MDC1 在功能上被鉴定为雄激素受体共激活剂，参与抑制前列腺癌
DOI：
10.1093/nar/gkv394
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发表时间：
2015-05-26
影响因子：
14.9
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Wang C;Sun H;Zou R;Zhou T;Wang S;Sun S;Tong C;Luo H;Li Y;Li Z;Wang E;Chen Y;Cao L;Li F;Zhao Y
DNA损伤检查点蛋白1（MDC1）是DNA损伤反应的重要介质。然而，MDC1在独立于DNA损伤的调节基因转录中的作用及其潜在机制尚未完全确定。雄激素受体（AR）是前列腺癌（PCa）的中心信号通路，其靶基因参与PCa的促发和抑制。在这里，我们在功能上鉴定了MDC 1作为AR的共激活剂。我们证明，MDC1促进AR和组蛋白乙酰转移酶GCN 5之间的关联，从而增加AR靶基因顺式调控元件上的组蛋白H3乙酰化水平。MDC1基因敲低促进PCa细胞生长和迁移。此外，在AR阳性PCa细胞系中，MDC1的消耗导致内源性雄激素诱导的靶基因的亚组的表达降低，包括细胞周期负调控因子p21和PCa转移抑制因子p21。MDC1和p21的表达与临床PCa的侵袭表型呈负相关。这些研究表明，MDC1作为表观遗传修饰因子调控AR的转录活性，MDC1可能是PCa的肿瘤抑制因子，为深入了解辅因子AR信号通路机制和MDC1在PCa中的作用提供了新的思路。
Mediator of DNA damage checkpoint protein 1 (MDC1) is essential for DNA damage response. However, the role of MDC1 in modulating gene transcription independently of DNA damage and the underlying mechanisms have not been fully defined. Androgen receptor (AR) is the central signaling pathway in prostate cancer (PCa) and its target genes are involved in both promotion and suppression of PCa. Here, we functionally identified MDC1 as a co-activator of AR. We demonstrate that MDC1 facilitates the association between AR and histone acetyltransferase GCN5, thereby increasing histone H3 acetylation level on cis-regulatory elements of AR target genes. MDC1 knockdown promotes PCa cells growth and migration. Moreover, depletion of MDC1 results in decreased expression of a subset of the endogenous androgen-induced target genes, including cell cycle negative regulator p21 and PCa metastasis inhibitor Vinculin, in AR positive PCa cell lines. Finally, the expression of MDC1 and p21 correlates negatively with aggressive phenotype of clinical PCa. These studies suggest that MDC1 as an epigenetic modifier regulates AR transcriptional activity and MDC1 may function as a tumor suppressor of PCa, and provide new insight into co-factor-AR-signaling pathway mechanism and a better understanding of the function of MDC1 on PCa.
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影响因子：
64.5
作者：
Garcia-Bassets, Ivan;Kwon, Young-Soo;Rosenfeld, Michael G.
通讯作者：
Rosenfeld, Michael G.
影响因子：
4.8
作者：
Lin, Tzu-Hua;Lee, Soo Ok;Chang, Chawnshang
通讯作者：
Chang, Chawnshang
影响因子：
11.2
作者：
Agoulnik, IU;Vaid, A;Weigel, NL
通讯作者：
Weigel, NL
影响因子：
11.1
作者：
Izumi K;Fang LY;Mizokami A;Namiki M;Li L;Lin WJ;Chang C
通讯作者：
Chang C
影响因子：
4.5
作者：
Bohgaki T;Bohgaki M;Cardoso R;Panier S;Zeegers D;Li L;Stewart GS;Sanchez O;Hande MP;Durocher D;Hakem A;Hakem R
通讯作者：
Hakem R