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Epigenetic control of skin homeostasis by the ULK3 nuclear kinase

ULK3核激酶对皮肤稳态的表观遗传控制

基本信息

批准号：
10453582
负责人：
GIAN-PAOLO DOTTO
金额：
$ 47.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453582
关键词：
Acetylation Address Affect Alleles Arginine Binding Biochemical Biological Assay Cell Differentiation process Cells Cervical Squamous Cell Carcinoma ChIP-seq Chromatin Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Coculture Techniques Cultured Cells DNA-Protein Interaction Dermal Development Differentiation and Growth Disease Management Drug Targeting Ensure Enzymes Epidermis Epigenetic Process Erinaceidae Fibroblasts Future GLI gene GLI2 gene Gene Deletion Gene Expression Gene Silencing Gene set enrichment analysis Genes Genetic Genetic Transcription Head and Neck Squamous Cell Carcinoma Head and neck structure Histone H3 Histones Homeostasis Human Immune In Vitro Individual Lesion Ligation Link Lung Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Mediating Metabolism Methylation Modeling Morbidity - disease rate Mus Nuclear Oncogenic Patients Pharmacology Phosphorylation Phosphotransferases Play Prevention Process Promoter Regions Protein-Arginine N-Methyltransferase Proteins Recurrent tumor Regulation Role Signal Pathway Signal Transduction Site Skin Skin Aging Skin Cancer Squamous cell carcinoma Stromal Cells Testing Tissues Toxic effect Transcriptional Regulation Transgenes Transgenic Mice UVB induced Ultraviolet B Radiation Work base carcinogenesis cell type clinically significant genetic signature in vivo inhibitor interest keratinocyte methylome organ transplant recipient overexpression prevent protein kinase inhibitor response self-renewal skin cancer prevention skin damage skin squamous cell carcinoma transcription regulatory network tumor progression tumorigenic

项目摘要

SUMMARY Field cancerization is a major clinical condition resulting from combined keratinocyte and dermal fibroblast alterations. Identification of regulatory molecules to target alterations of both cell types is of substantial interest. We propose that the nuclear kinase ULK3 is one such a molecule, which we previously studied for its role in fibroblasts. Here we will pursue the following aims: (1) We will test the hypothesis that ULK3 impinges on key transcription regulatory networks determining keratinocyte self-renewal and oncogenic potential. ULK3 is up- regulated in keratinocyte-derived skin and head/neck Squamous Cell Carcinomas (SCCs) and silencing of the gene suppresses proliferative and tumorigenic potential of both human keratinocytes (HKCs) and SCC cells. We will explore the interplay between ULK3 and the p63 and GLI transcription networks in growth/differentiation of these cells and their oncogenicity, in orthotopic models of skin cancer expansion. 2) We will test the hypothesis that ULK3 functions at the intersection between the arginine methylome and chromatin organization. Arginine methylation is a little investigated mode of chromatin regulation in SCCs development. We have found that ULK3 associates with the arginine methylases PRMT1 and PRMT5 (PRMTs) and that ULK3 loss in SCC cells results in down-modulation of di-methylated forms of Histone 4 (H4R3), well established products of PRMTs activity. We will test whether ULK3 controls PRMT1 and 5 activity and/or links these enzymes to key substrates such as p63, GLI2 and histones (specifically H4). We will further determine whether ULK3 control of gene transcription in HKCs and SCC involves a broader impact on chromatin organization through convergent PRMT1- and 5- dependent mechanisms. 3) We will test the hypothesis that ULK3 is a target of translational relevance for skin field cancerization. We will undertake a dual genetic and pharmacological approach. Genetically, we have developed mice with Ulk3flox alleles and K14- CreER transgene for keratinocyte-specific Ulk3 deletion. We will examine the impact of Ulk3 deletion on normal skin homeostasis and, after transfer into an albino hairless background, assess the consequences for UVB-induced skin field cancerization. Pharmacologically, we found that ULK3 inhibitory compounds suppress proliferative potential of SCC cells as well as cancer/stromal cell expansion. We will extend our studies with ULK3 and PRMT1/5 inhibitors on cultured cells and further test the most promising compounds in an in vivo orthotopic model of skin cancer/stromal cells expansion.

总结现场癌变是一个主要的临床条件，导致角质形成细胞和真皮成纤维细胞相结合改变。鉴定靶向两种细胞类型的改变的调节分子具有实质性的意义。我们认为核激酶ULK 3就是这样一种分子，我们以前研究过它在细胞凋亡中的作用。成纤维细胞本文的主要目的是：（1）检验ULK 3与密钥冲突的假设转录调控网络决定角质形成细胞的自我更新和致癌潜力。ULK 3已启动- 在角化细胞衍生的皮肤和头颈鳞状细胞癌（SCC）中调节，该基因抑制人角质形成细胞（HKC）和SCC细胞的增殖和致瘤潜力。我们将探讨ULK 3和p63和GLI转录网络在生长/分化中的相互作用。这些细胞和它们的致癌性，在皮肤癌扩展的原位模型中。2)我们将检验这个假设 ULK 3在精氨酸甲基化组和染色质组织之间的交叉处起作用。精氨酸甲基化是SCC发育中染色质调控的一种研究较少的模式。我们发现ULK 3 与精氨酸甲基化酶PRMT 1和PRMT 5（PRMT）相关，SCC细胞中ULK 3的缺失导致下调组蛋白4（H4 R3）的二甲基化形式，这是PRMT活性的公认产物。我们将测试ULK 3是否控制PRMT 1和5的活性和/或将这些酶与关键底物，如 p63、GLI 2和组蛋白（特别是H4）。我们将进一步确定ULK 3是否控制基因转录在HKC和SCC中，通过聚合PRMT 1-和5- 依赖机制。3)我们将检验ULK 3是皮肤翻译相关的靶标这一假设现场癌变我们将采取遗传学和药理学双重方法。从遗传学上讲，开发了具有Ulk 3flox等位基因和用于角质形成细胞特异性Ulk 3缺失的K14- CreER转基因的小鼠。我们将检查Ulk 3缺失对正常皮肤稳态的影响，并在转移到无毛发的白化病患者中后，背景，评估UVB诱导的皮肤区域癌变的后果。从药理学上讲，我们发现 ULK 3抑制性化合物抑制SCC细胞以及癌/基质细胞的增殖潜力扩张.我们将用ULK 3和PRMT 1/5抑制剂在培养细胞上扩展我们的研究，并进一步测试ULK 3和PRMT 1/5抑制剂的作用。在皮肤癌/基质细胞扩增的体内原位模型中最有前途的化合物。