Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth
Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth
复制标题
DOI：
10.1038/emboj.2011.154
复制
发表时间：
2011-06-15
期刊：
影响因子：
11.4
通讯作者：
Wang, Qianben
中科院分区：
文献类型：
--
作者：
Chen, Zhong;Zhang, Chunpeng;Wang, Qianben
UBE2C癌基因在许多类型的实体肿瘤中过度表达，包括致死性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不完全清楚。在这里，我们发现CRPC特异性增强子在ar阴性和阳性CRPC细胞中都驱动UBE2C过表达。我们进一步表明，UBE2C增强子/启动子的远程相互作用需要协同激活子MED1的募集。重要的是，我们发现med1介导的染色质环的分子机制涉及PI3K/AKT磷酸化med1介导的FoxA1、RNA聚合酶II和TATA结合蛋白的募集以及它们随后在UBE2C位点的相互作用。MED1磷酸化导致UBE2C位点环化、UBE2C基因表达和细胞生长。我们的研究结果不仅确定了协同激活子（MED1）的翻译后修饰（磷酸化）在形成或维持活性染色质结构中的因果作用，而且还表明开发针对CRPC的特异性治疗方法应考虑靶向磷酸化的MED1。EMBO杂志，2011,30,2405-2419。doi: 10.1038 / emboj.2011.154;2011年5月10日在线发布
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. The EMBO Journal (2011) 30, 2405-2419. doi: 10.1038/emboj.2011.154; Published online 10 May 2011