Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell-cell and cell-matrix adhesion programmes. However, limited knowledge exists on the relevant cell-cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell-cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell-cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.

中文翻译：

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ZNF185是p63靶基因，对表皮分化和鳞状细胞癌的发展至关重要。

健康的分层上皮细胞的发育和维持需要复杂的转录程序的协调。转录因子p63是p53家族的成员，在上皮发育和体内平衡中起着至关重要的作用。对p63依赖性转录组的分析表明，p63在上皮发育中功能的一个重要方面是细胞-细胞和细胞-基质粘附程序的调节。然而，关于参与生理上皮形成的相关细胞-细胞粘附分子的知识有限。同样，只有有限的数据可用来了解细胞-细胞粘附程序的失调在肿瘤形成中是否重要。在这里，使用表皮作为RNA测序方法的实验模型，我们确定了分化过程中诱导的新型p63调控基因，ZNF185。ZNF185是与肌动蛋白细胞骨架相关的Lin-1，Is-1和Mec-3（LIM）域的蛋白质，其功能鲜为人知。我们发现p63绑定到特定的增强子区域，促进其表达以维持上皮分化。根据基因阵列分析，ZNF185沉默会严重损害角质形成细胞的分化。ZNF185在与E-cadherin物理相互作用的细胞-细胞外围被检测到，这表明保持上皮完整性超出其促分化作用非常重要。有趣的是，分化差，包括头颈部，宫颈和食道鳞状细胞癌显示ZNF185表达缺失。一起，