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Understanding the mechanism of H3K9 HMT mediated suppression of melanoma

了解 H3K9 HMT 介导的黑色素瘤抑制机制

基本信息

批准号：
9767742
负责人：
Raul J. Martinez-McFaline
金额：
$ 5万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-12 至 2020-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767742
关键词：
Affect Alleles BRAF gene Brain Sarcoma Candidate Disease Gene Cell Line Cells Cessation of life Childhood Brain Neoplasm DNA Sequence Alteration Disease EZH2 gene Enzymes Epigenetic Process Family Gene Expression Gene Silencing Genes Genetic Guide RNA Histones Human Individual Lysine Maintenance Malignant Neoplasms Mediating Melanoma Cell Metastatic to Methionine Methylation Methyltransferase Modeling Molecular Mutation Oncogenes Oncogenic Patients Pharmacology Phenotype Pigments Play Proteins Recurrence Research Proposals Role SETDB1 gene SWI/SNF Family Complex Signal Transduction Skin Cancer Survival Rate Testing Transgenes Zebrafish cell type drug development epigenome genome editing histone demethylase histone methylation histone methyltransferase in vivo interest loss of function melanocyte melanoma metaplastic cell transformation new therapeutic target novel novel therapeutics overexpression progenitor tool tumor tumor initiation tumorigenesis

项目摘要

PROJECT SUMMARY Alterations in the epigenome have been associated with changes in cellular identity and have emerged as important drivers in human cancer. In melanoma, we have shown that overexpression of SETDB1 and SUV39H1, two histone 3 lysine 9 methyltransferases (H3K9 HMTs), accelerate melanoma formation in zebrafish and are also amplified in human cases. Recently, our lab has used the histone 3 lysine-to-methionine mutation at K9 (H3.3K9M) to interrogate the consequences of H3K9 HMT loss of function. Remarkably, we find that expression of H3.3K9M suppresses tumor onset. Because histone methylation is known to play a critical role in proper maintenance of cellular identity, we hypothesize that loss of H3K9 HMT activity suppresses melanoma through inhibition of the progenitor phenotype, which has been shown to promote melanomagenesis. We propose using both zebrafish and human melanoma cell lines to identify the mechanisms through which loss of H3K9 HMT activity suppresses melanoma formation.

项目摘要表观基因组的改变与细胞身份的变化有关，成为人类癌症的重要驱动因素。在黑色素瘤中，我们已经证明， SETDB 1和SUV 39 H1，两种组蛋白3赖氨酸9甲基转移酶（H3K9 HMT），在斑马鱼中形成黑色素瘤，并且在人类病例中也被放大。最近，我们的实验室使用了组蛋白3 K9（H3.3K9M）处的赖氨酸至甲硫氨酸突变，以询问 H3K9 HMT功能丧失。值得注意的是，我们发现H3.3K9M的表达抑制了肿瘤的生长，发病因为已知组蛋白甲基化在细胞的正常维持中起关键作用，同一性，我们假设H3K9 HMT活性的丧失通过抑制祖细胞表型，这已被证明是促进黑色素瘤。我们建议使用斑马鱼和人类黑色素瘤细胞系，以确定细胞丢失的机制 H3K9 HMT活性抑制黑色素瘤形成。