Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
J Clin Invest. 2018 Jun 1;128(6):2581-2599. doi: 10.1172/JCI96915. Epub 2018 May 14.
Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment.
Notch1/2 基因在鳞状细胞癌（SCC）中发挥肿瘤抑制作用，SCC 是皮肤和内脏器官中非常常见的恶性肿瘤。与 Notch 相反，我们发现转录因子 CSL（也称为 RBP-Jκ）在 SCC 发展中发挥促肿瘤作用，CSL 是经典 Notch 信号的关键效应因子，具有内在的转录抑制功能。该基因在表皮上层和进行分化的人角质形成细胞（HKC）中表达减少，而在皮肤、头颈部和肺部的癌前和恶性 SCC 病变中表达增加。CSL 水平的增加增强了 HKC 和 SCC 细胞的增殖潜力，而 CSL 的沉默诱导了生长停滞和细胞凋亡。在体内，具有较高 CSL 水平的 SCC 细胞会产生快速扩张的肿瘤，而沉默 CSL 的细胞形成较小且分化程度较高的肿瘤，并伴有增强的炎症浸润。沉默 CSL 的 HKC 和 SCC 细胞的全转录组分析显示，凋亡、细胞周期和促炎基因发生了主要的调节。我们还表明，组蛋白去甲基化酶 KDM6B 是 CSL 的直接靶标，CSL 在 HKC 和 SCC 增殖能力、肿瘤发生和肿瘤相关炎症反应中起相反的作用。CSL/KDM6B 蛋白表达可作为 SCC 发展的生物标志物和癌症治疗的指标。
