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.

抽象的组蛋白修饰子是所有形式的癌症中突变程度最高的基因之一，其中组蛋白去甲基化酶 UTX (KDM6A) 是最常见的酶之一。 UTX 在多种上皮癌中发生突变包括皮肤鳞状细胞癌 (cSCC)，这是所有人类中第二常见的类型恶性肿瘤。 UTX 存在于 X 染色体上，是主要的增强子调节因子。它建立了主动通过其组蛋白去甲基化酶活性以及与其他物质复合的能力来增强子景观激活组蛋白修饰剂。 UTX 还可以逃避 X 失活，从而造成剂量差异男性和女性可能解释了在风险和风险方面观察到的一些性别特异性差异某些类型癌症的严重程度，包括鳞状细胞癌。为了支持这一点，当所有在组织中，UTX 损失会导致所有雌性胚胎死亡，而约 25% 的雄性存活至成年。有趣的是，UTY，UTX 的 Y 连锁旁系同源物，保留了最小的去甲基化酶功能，但可能通过其他机制补偿UTX的损失。除了涉及特定性别之外尽管存在差异，UTX 在多种上皮癌中被认为是一种肿瘤抑制因子。最近，UTX还已被证明能够感知细胞的氧气。越来越多的数据表明 UTX 对于正常的细胞功能至关重要体内平衡并在发育和癌变中发挥重要作用。然而，尽管有这些证据以及 cSCC 中 UTX 突变的高发生率，实际上人们不了解这种酶如何在表皮稳态和癌发生过程中发挥作用。为了研究这一点，我们培育了具有 Utx 的表皮特异性缺失，只有雌性 Utx 敲除小鼠表现出明显的异常。具体来说，纯合基因敲除雌性小鼠体型缩小，皮肤呈红斑、鳞状。与同窝对照相比。从这些小鼠身上采集的皮肤进行 H&E 染色显示癌前病变表皮增生等变化。当在原代人角质形成细胞中被击倒时，UTX 损失会导致到戏剧性的转录变化。缺氧反应基因和涉及氧化磷酸化的基因是其中表达差异最大。这些数据引发了这样的假设：UTX 对于正常的健康至关重要。稳态基因表达，当失去时会导致新陈代谢改变和更高的癌症风险。为了测试这个假设，我将实现以下目标：在 Aim1 中，我将确定 Utx 损失如何影响表皮体内稳态并研究其在表皮缺氧和代谢中的作用。在 Aim2 中我将使用 UV- 在我们的 Utx 敲除小鼠模型中使用辐射诱导肿瘤发生，以确定 Utx 是否充当肿瘤表皮中的抑制因子。我还将评估 Utx 丢失对肿瘤风险和严重程度的影响男性和女性收集有关 UTX 复制基因剂量驱动的性别特异性差异的见解。此外，鉴于表观遗传变化固有的可逆性，这些研究有望提供新的深入了解表观遗传疗法治疗这些极其常见的癌症的潜力。