权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role of UTX in Epidermal Homeostasis, Carcinogenesis, and Sex Mediated Risk of Cutaneous Squamous Cell Carcinoma

UTX 在表皮稳态、癌变和性介导的皮肤鳞状细胞癌风险中的作用

基本信息

批准号：
10311627
负责人：
Gina Pacella
金额：
$ 4.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2021-07-14 至 2024-07-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311627
关键词：
Acute Adult Affect Biological Assay Carcinoma Cell Culture Techniques Cell Differentiation process Cell Proliferation Cells Chromatin Complex Data Data Pooling Development Disease Embryo Enhancers Enzymes Epidermis Epigenetic Process Epithelial Equilibrium Fatality rate Female Functional disorder Gene Dosage Gene Expression Gene Expression Regulation Genes Genetic Transcription Glean Glycolysis Harvest High-Risk Cancer Histologic Histones Homeostasis Human Hyperplasia Hypoxia In Vitro Incidence Knock-out Knockout Mice Lead Link Lysine Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Mediating Metabolic Metabolism Methylation Mitochondria Modeling Monitor Mus Mutate Mutation Neoplasms Oxidative Phosphorylation Oxygen Oxygen Consumption Phenotype Play Premalignant Change Preneoplastic Change Regulator Genes Respiration Risk Role Severities Sex Differences Skin Speed Stains Structure Testing Therapeutic Tissues Treatment Cost Tumor Suppressor Proteins Ultraviolet B Radiation Ultraviolet Rays United States X Chromosome X Inactivation cancer risk cancer type carcinogenesis cellular development differential expression dosage epigenetic regulation epigenetic therapy histone demethylase histone modification in vivo insight keratinocyte knock-down loss of function mutation male melanoma men mitochondrial metabolism mouse model paralogous gene prevent programs recruit response self-renewal sensor sex skin squamous cell carcinoma transcriptome sequencing tumor tumorigenesis virtual

项目摘要

ABSTRACT Histone modifiers are amongst the most highly mutated genes in all forms of cancer, with the histone demethylase UTX (KDM6A) being one of the most frequent. UTX is mutated in several epithelial cancers including cutaneous squamous cell carcinoma (cSCC), the second most common type of all human malignancies. UTX is found on the X chromosome and is a major enhancer regulator. It establishes the active enhancer landscape through its histone demethylase activity as well as its ability to complex with other activating histone modifiers. UTX is also known to escape X inactivation creating a dosage disparity between males and females that may account for some of the sex specific differences observed for both the risk and severity of certain types of cancer, including cSCC. In support of this, when constitutively knocked out in all tissues, UTX loss results in embryonic lethality in all females, while ~25% of males survive to adulthood. Interestingly, UTY, the Y-linked paralog of UTX, retains minimal demethylase function but potentially compensates for loss of UTX through other mechanisms. In addition to its involvement in sex specific differences, UTX is implicated as a tumor suppressor in several epithelial cancers. Recently, UTX has also been shown to sense cellular oxygen. Accumulating data suggests that UTX is critical for proper cellular homeostasis and plays fundamental roles in development and carcinogenesis. However, despite this evidence and the high incidence of UTX mutations in cSCC, there is virtually no understanding of how this enzyme functions during epidermal homeostasis and carcinogenesis. To investigate this, we have generated mice with epidermal specific deletions of Utx where only female Utx knockout mice display any obvious abnormalities. Specifically, homozygous knockout female mice present with reduced size as well as erythematous, scaly skin compared to littermate controls. H&E staining of the skin harvested from these mice reveals premalignant changes such as epidermal hyperplasia. When knocked down in primary human keratinocytes UTX loss leads to dramatic transcriptional changes. Hypoxic response genes and those involved oxidative phosphorylation are among the most differentially expressed. These data provoke the hypothesis that UTX is critical for the proper homeostatic gene expression, and when lost lead to altered metabolism and higher cancer risk. To test this hypothesis, I will carry out the following aims: In Aim1 I will determine how Utx loss affects epidermal homeostasis in vivo and investigate its role in hypoxia and metabolism in the epidermis. In Aim2 I will use UV- radiation to induce tumorigenesis in our Utx knockout mouse model to determine if Utx acts as a tumor suppressor in the epidermis. I will also assess how tumor risk and severity is affected by Utx loss between males and females to glean insights about sex specific differences driven by UTX copy gene dosage. Furthermore, given the inherent reversibility of epigenetic changes, these studies hold promise to provide new insight into the potential for epigenetic therapies for these incredibly common cancers.

摘要