Polycomb proteins and skin cancer prevention

描述（申请人提供）：表皮鳞状细胞癌是人类最常见的癌症之一，发病率呈上升趋势。因此，皮肤癌是一个重要的健康问题，晚期疾病复发，危及生命和毁容。由于皮肤癌的发展涉及长期的多种事件，预防是一个重要和首选的选择。由于这个原因，人们正在努力确定可以口服或涂在皮肤表面的预防药物。我们特别关注了从西兰花中提取的萝卜硫素（SFN）对Ezh2 Polycomb Group （PcG）蛋白功能的影响。PcG蛋白是一种重要的表观遗传调控因子，其甲基化和泛素化特异性组蛋白以产生封闭的染色质并沉默肿瘤抑制基因的表达。包括Ezh2在内的关键多梳蛋白在皮肤癌中过度表达，这导致p21Cip1和其他肿瘤抑制因子沉默，从而提高肿瘤细胞存活率。我们已经证明SFN抑制Ezh2，导致p21Cip1表达增加。这些变化最终导致皮肤癌细胞增殖停止和癌细胞死亡增加。我们激动人心的未发表的初步研究表明，包括角质形成细胞存活和干细胞命运的两个主要调节因子DNp63a和KLF4的途径调节Ezh2水平。这些蛋白质以前没有被认为是重要的预防靶点。我们推测，在癌细胞中，DNp63a、KLF4通路刺激Ezh2基因的表达，从而降低p21Cip1的表达，从而提高癌细胞的存活率。我们进一步提出SFN通过抑制该通路中的事件来降低Ezh2的表达并增加肿瘤抑制因子的表达。本提案中的实验围绕着明确的翻译相关目标。特异性目的1研究DNp63a和KLF4如何调控Ezh2水平。Specific Aims 2研究SFN对这一途径的调控。特异性Aim 3研究Ezh2对p21Cip1表达的调节，特异性Aim 4研究Ezh2和SFN治疗对体内肿瘤形成的影响。这些研究与了解SFN在预防皮肤癌形成中的生物学作用高度相关。

DESCRIPTION (provided by applicant): Epidermal squamous cell carcinoma is one of the most common forms of human cancer and the incidence is increasing. Thus, skin cancer is an important health concern and advanced disease recurs and is life- threatening and disfiguring. Because skin cancer development involves multiple events over a long period of time, prevention is an important and preferred option. For this reason there is a major ongoing effort to identify preventive agents that can be taken orally or applied on the skin surface. In particula, we have focused on the impact of sulforaphane (SFN), derived from broccoli, on function of the Ezh2 Polycomb Group (PcG) protein. PcG proteins are important epigenetic regulators that methylate and ubiquitinate specific histones to produce closed chromatin and silence tumor suppressor gene expression. Key polycomb group proteins, including Ezh2, are overexpressed in skin cancer and this drives silencing of p21Cip1 and other tumor suppressors leading to enhanced tumor cell survival. We have shown that SFN suppresses Ezh2 which leads to increased p21Cip1 expression. These changes ultimately lead to cessation of skin cancer cell proliferation and increased cancer cell death. Our exciting unpublished preliminary studies suggest that a pathway that includes two master regulators of keratinocyte survival and stem cell fate, DNp63a and KLF4, regulates Ezh2 level. These proteins have not been previously considered as important prevention targets. We hypothesize that in cancer cells a DNp63a, KLF4 pathway stimulates Ezh2 gene expression which, in turn, acts to reduce p21Cip1 expression leading to increased cancer cell survival. We further propose that SFN inhibits events in this pathway to reduce Ezh2 expression and increase tumor suppressor expression. Experiments in this proposal revolve around well-defined translation-relevant goals. Specific Aim 1 studies how DNp63a and KLF4 regulate Ezh2 level. Specific Aims 2 examines SFN regulation of this pathway. Specific Aim 3 examines Ezh2 regulation of p21Cip1 expression, and Specific Aim 4 address the impact of Ezh2 and SFN treatment on tumor formation in vivo. These studies are highly relevant to understanding the biological role of SFN in preventing skin cancer formation.