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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：
10296312
负责人：
GIAN-PAOLO DOTTO
金额：
$ 47.71万
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/10296312
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 Organ Transplantation 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 Transplant Recipients UVB induced Ultraviolet B Radiation Work base carcinogenesis cell type clinically significant genetic signature in vivo inhibitor/antagonist interest keratinocyte methylome overexpression prevent protein kinase inhibitor response self-renewal skin cancer prevention skin damage skin squamous cell carcinoma 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