Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH, USA.
EMBO J. 2011 May 10;30(12):2405-19. doi: 10.1038/emboj.2011.154.
The UBE2C oncogene is overexpressed in many types of solid tumours including the lethal castration-resistant prostate cancer (CRPC). The underlying mechanisms causing UBE2C gene overexpression in CRPC are not fully understood. Here, we show that CRPC-specific enhancers drive UBE2C overexpression in both AR-negative and -positive CRPC cells. We further show that co-activator MED1 recruitment to the UBE2C enhancers is required for long-range UBE2C enhancer/promoter interactions. Importantly, we find that the molecular mechanism underlying MED1-mediated chromatin looping involves PI3K/AKT phosphorylated MED1-mediated recruitment of FoxA1, RNA polymerase II and TATA binding protein and their subsequent interactions at the UBE2C locus. MED1 phosphorylation leads to UBE2C locus looping, UBE2C gene expression and cell growth. Our results not only define a causal role of a post-translational modification (phosphorylation) of a co-activator (MED1) in forming or sustaining an active chromatin structure, but also suggest that development of specific therapies for CRPC should take account of targeting phosphorylated MED1.
UBE2C 癌基因在许多实体肿瘤中过表达，包括致命的去势抵抗性前列腺癌（CRPC）。导致 CRPC 中 UBE2C 基因过表达的潜在机制尚未完全阐明。在这里，我们表明 CRPC 特异性增强子驱动 AR 阴性和阳性 CRPC 细胞中 UBE2C 的过表达。我们进一步表明，共激活因子 MED1 募集到 UBE2C 增强子对于长距离 UBE2C 增强子/启动子相互作用是必需的。重要的是，我们发现 MED1 介导的染色质环looping 的分子机制涉及 PI3K/AKT 磷酸化的 MED1 介导的 FoxA1、RNA 聚合酶 II 和 TATA 结合蛋白的募集及其随后在 UBE2C 基因座上的相互作用。MED1 磷酸化导致 UBE2C 基因座环looping、UBE2C 基因表达和细胞生长。我们的研究结果不仅定义了一种翻译后修饰（磷酸化）的共激活因子（MED1）在形成或维持活性染色质结构中的因果作用，而且还表明，针对 CRPC 的特定治疗方法的开发应考虑靶向磷酸化的 MED1。
