Epigenetic Regulators in Epidermal Neoplasia

表皮肿瘤中的表观遗传调节因子

• 批准号: 7970931
• 负责人: Vanessa LopezPajares
• 金额: $ 4.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-11-16 至 2011-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7970931
• 关键词: Address; Calcium; Cancer cell line; Cell physiology; Complex; Cytoplasm; Development; Differentiation and Growth; Disease; EZH2 gene; Enzymes; Epigenetic Process; Future; Gene Activation; Gene Expression; Gene Silencing; Genes; Health; Histone H3; Histones; Homeostasis; Human; Link; Lysine; Maintenance; Malignant Neoplasms; Mediating; Methylation; Methyltransferase; Modeling; Modification; Neoplasms; Pattern; Plasmids; Play; Polycomb; Population; Proteins; RNA Interference; Recruitment Activity; Regulation; Repression; Research Design; Role; Squamous cell carcinoma; Stem cells; Testing; Tissues; Tumor Suppressor Proteins; cell type; chromatin modification; demethylation; design; gain of function; gene repression; histone methyltransferase; histone modification; in vivo; insight; keratinocyte; loss of function; mutant; novel; overexpression; prevent; protein expression; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Background/Objective: Epigenetic regulators control gene expression patterns and have been shown to regulate epidermal differentiation. Modifications of chromatin, for example, methylation, are associated with gene repression as well as activation. The Polycomb group (PcG) proteins tri-methylate histone H3 lysine 27 generating a repressive mark on epidermal differentiation genes and maintaining a proliferative state. This action is opposed by the JMJD3 histone demethylase, which removes these tri-methyl marks and activates epidermal gene expression. Progression of epidermal neoplasias are characterized by loss of differentiation. Thus, we propose that the histone demethylase JMJD3 is a critical player in cancer and loss of function of JMJD3 contributes to progression to epidermal squamous cell carcinoma. Conversely, we propose that the PcG protein, EZH2, whose methyltransferase activity maintains a proliferative state and opposes JMJD3 function, is also involved in progression to invasive squamous cell carcinoma. In support of this idea, overexpression of EZH2 has been observed in a number of cancers. Specific Aims and Research Design: (I) Characterization of JMJD3 function in epidermal neoplasia: (lA) Induction of epidermal neoplasia under altered JMJD3 function; (IB) Determine the contribution of JMJD3 subcellular localization to induction of epidermal neoplasia; (IC) Analysis of JMJD3 function in neoplasia. (II) Determination of the role of PcG protein EZH2 in epidermal neoplasia: (IIA) Induction of epidermal neoplasia with functionally altered EZH2; (IIB) EZH2 impacts on progression of epidermal neoplasia. Loss of function of JMJD3 and EZH2 will be obtained by RNA interference and enzyme-deficient mutants; and gain of function will be obtained by introduction of wild-type protein. Both RNAi and protein expression plasmids will be introduced retrovirally into keratinocytes. We will use a Ras-driven epidermal neoplasia model that is well established in our lab to architecturally recapitulate neoplasia in vivo and assess the role of JMJD3 and EZH2 in tumor progression. PUBLIC HEALTH RELEVANCE: Cancer progression is characterized by loss of cellular differentiation. This proposal seeks to understand mechanisms controlling epidermal growth and differentiation. Abnormalities of epidermal homeostasis include diseases exerting negative impacts on a large portion of the US population, such as squamous cell carcinoma. The current proposal is designed to provide insight and identify targets for the development of future therapies for epidermal cancer.

描述（由申请人提供）：背景/客观：表观遗传调节器控制基因表达模式，并已被证明可以调节表皮分化。 染色质的修饰，例如甲基化，与基因抑制和激活有关。 Polycomb组（PCG）蛋白三甲基酸组蛋白H3赖氨酸27在表皮分化基因上产生抑制标记并维持增生状态。 这种作用与JMJD3组蛋白脱甲基酶相反，该脱甲基酶去除这些三甲基标记并激活表皮基因表达。 表皮肿瘤的进展的特征是分化的丧失。 因此，我们建议组蛋白脱甲基酶JMJD3是癌症的关键参与者，JMJD3功能的丧失有助于向表皮鳞状细胞癌发展。 相反，我们建议PCG蛋白EZH2的甲基转移酶活性保持增殖状态并反对JMJD3功能，他也参与了侵入性鳞状细胞癌的发展。 为了支持这一想法，已经在许多癌症中观察到EZH2的过表达。 具体目的和研究设计：（i）表皮肿瘤中JMJD3功能的表征：（LA）在变化的JMJD3功能下，表皮肿瘤的诱导； （IB）确定JMJD3亚细胞定位对诱导表皮肿瘤的贡献； （IC）分析肿瘤中JMJD3功能。 （ii）确定PCG蛋白EZH2在表皮肿瘤中的作用：（IIA）诱导表皮肿瘤，其功能改变EZH2； （IIB）EZH2影响表皮肿瘤的进展。 JMJD3和EZH2功能的损失将通过RNA干扰和缺陷酶突变体获得。并通过引入野生型蛋白来获得功能的增益。 RNAi和蛋白表达质粒均将逆转录病毒引入角质形成细胞。 我们将使用由RAS驱动的表皮肿瘤模型，该模型在我们的实验室中良好建立，以在体内概括肿瘤，并评估JMJD3和EZH2在肿瘤进展中的作用。 公共卫生相关性：癌症进展的特征是细胞分化的丧失。 该提案旨在了解控制表皮生长和分化的机制。 表皮稳态异常包括对美国大部分人群（例如鳞状细胞癌）造成负面影响。 当前的提案旨在提供洞察力并确定针对表皮癌的未来疗法开发的目标。