Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer
Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer
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DOI：
10.1172/jci72718
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发表时间：
2014-05-01
影响因子：
15.9
通讯作者：
Dotto, G. Paolo
中科院分区：
文献类型：
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作者：
Brooks, Yang Sui;Ostano, Paola;Dotto, G. Paolo
编码NOTCH1的基因的表达下调或功能丧失突变与皮肤和内脏器官中鳞状细胞分化功能障碍和鳞状细胞癌（SCC）的发展相关。虽然NOTCH1受体的活化已经得到很好的表征，但对NOTCH1基因转录是如何调控的知之甚少。使用生物信息学和功能筛选方法，我们确定了角质形成细胞中NOTCH 1基因的几种调节因子，转录因子DLX5和EGR3以及雌激素受体β（ER β）直接控制其在分化中的表达。DLX5和ERG 3是将RNA聚合酶II（PolII）募集到NOTCH 1基因座所必需的，而ER β通过RNA Poll暂停释放来控制NOTCH 1转录。在皮肤、头颈部和肺SCC以及SCC衍生的细胞系中，包括ER β在内的几种已鉴定的NOTCH1调节剂的表达经常受到损害。此外，角质形成细胞ER β依赖的基因表达程序在来自不同身体部位的SCC中被颠覆，并且女性与男性患者的头颈部和肺SCC的突变和基因表达特征存在一致的差异。实验性增加ER β表达或用ER β激动剂处理抑制SCC细胞增殖，并促进NOTCH 1表达和鳞状分化，无论是在体外还是在小鼠异种移植物中。我们的数据确定了角质形成细胞中NOTCH1表达的转录控制与雌激素反应之间的联系，这对鳞状细胞癌的分化治疗具有意义。
Downxnodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor beta (ER beta) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ER beta controls NOTCH1 transcription through RNA Poll pause release. Expression of several identified NOTCH1 regulators, including ER beta is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ER beta-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ER beta expression or treatment with ER beta agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.