Wang Chunyu, Sun Hongmiao, Zou Renlong, Zhou Tingting, Wang Shengli, Sun Shiying, Tong Changci, Luo Hao, Li Yanshu, Li Zhenhua, Wang Enhua, Chen Yuhua, Cao Liu, Li Feng, Zhao Yue
Department of Cell Biology, Key laboratory of Cell Biology, Ministry of Public Health, and Key laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China.
Department of Urology, the First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, China.
Nucleic Acids Res. 2015 May 26;43(10):4893-908. doi: 10.1093/nar/gkv394. Epub 2015 Apr 30.
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.
DNA损伤检查点蛋白1（MDC1）是DNA损伤反应所必需的。然而，MDC1在独立于DNA损伤的情况下调节基因转录的作用及其潜在机制尚未完全明确。雄激素受体（AR）是前列腺癌（PCa）的核心信号通路，其靶基因参与PCa的促进和抑制。在这里，我们在功能上鉴定MDC1为AR的共激活因子。我们证明MDC1促进AR与组蛋白乙酰转移酶GCN5之间的结合，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敲低促进PCa细胞的生长和迁移。此外，在AR阳性PCa细胞系中，MDC1的缺失导致内源性雄激素诱导的靶基因子集的表达降低，包括细胞周期负调节因子p21和PCa转移抑制因子纽蛋白。最后，MDC1和p21的表达与临床PCa的侵袭性表型呈负相关。这些研究表明，MDC1作为一种表观遗传修饰因子调节AR转录活性，MDC1可能作为PCa的肿瘤抑制因子，并为辅助因子-AR信号通路机制提供了新的见解，有助于更好地理解MDC1在PCa中的功能。
