Abstract：
The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.
摘要：
基底谱系特征的存在表明乳腺高侵袭性人类腺癌，膀胱和胰腺。然而,维持这种异常细胞状态的生化机制知之甚少。在这里，我们进行了基于标记的遗传筛选，以寻找维持胰腺导管腺癌（PDAC）基础同一性所需的因素。这种方法揭示了MED12是这种疾病中基底细胞状态的强大调节剂。使用生化重建和表观基因组学，我们表明MED12通过桥接转录因子ΔNp63（一种已知的基础谱系的主调节因子）来实现这一功能，用介体复合物激活谱系特异性增强子元件。与这一发现一致，与缺乏基础特征的PDAC细胞相比,基底样PDAC的生长对MED12损失过敏。一起来看,我们的基因筛选揭示了在人类癌症中维持基本身份的生化相互作用，它可以作为肿瘤谱系定向疗法的靶标。
