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，其发病率正在上升。因此，皮肤癌是一个重要的健康问题，晚期疾病会复发，危及生命和毁容。由于皮肤癌的发展涉及长时间内的多个事件，因此预防是一个重要和首选的选择。出于这个原因，目前正在进行一项重大努力，以确定可以口服或涂抹在皮肤表面的预防药物。特别是，我们重点研究了西兰花中提取的萝卜硫素(SFN)对Ezh2多梳基(PcG)蛋白功能的影响。PCG蛋白是重要的表观遗传调节因子，甲基化和泛素化特定的组蛋白以产生封闭的染色质和沉默肿瘤抑制基因的表达。包括Ezh2在内的关键多梳组蛋白在皮肤癌中过表达，这会导致p21Cip1和其他肿瘤抑制因子的沉默，从而提高肿瘤细胞的存活率。我们已经证明SFN抑制Ezh2，从而导致p21Cip1表达增加。这些变化最终导致皮肤癌细胞停止增殖，增加癌细胞死亡。我们令人兴奋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目标。我们假设，在癌细胞中，DNp63a，KLF4途径刺激Ezh2基因表达，进而降低p21Cip1的表达，从而提高癌细胞的存活率。我们进一步认为SFN抑制该通路中的事件，从而减少Ezh2的表达，增加抑癌基因的表达。这项建议中的实验围绕着明确定义的与翻译相关的目标。具体目的1研究DNp63a和KLF4对Ezh2水平的调节作用。特异性AIMS 2研究了SFN对这一途径的调控。特异性目标3检测Ezh2对p21Cip1表达的调节，特异性目标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 Our exciting unpublished preliminary studies suggest that a pathway that includes two master regulators of keratinocyte survival and stem cell fate, DNp63a and KLF4, regulates Ezh2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.