Elucidating the role of REST in shaping the epigenome of melanoma

阐明 REST 在塑造黑色素瘤表观基因组中的作用

基本信息

批准号：
10198753
负责人：
Christie Bao Thu Nguyen
金额：
$ 4.44万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-18 至 2024-06-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198753
关键词：
Address Apoptosis Architecture Automobile Driving BRAF gene Binding Biological Assay Cadherins Cell Cycle Cell Cycle Arrest Cell Line Cell physiology Cells Cessation of life Chromatin Complex Coupled DNA DNA Binding Data Dependence Development Diagnosis Disease Distant Elements Enhancers Epigenetic Process Excision Exhibits Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Genetic Transcription Genomic approach Genomics Growth High-Throughput Nucleotide Sequencing Histones Human Immunotherapy Impairment Incidence Investigation Laboratories Lead MEKs Malignant Neoplasms Mediating Melanoma Cell Metastatic Melanoma Molecular Neural Crest Cell Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neuroglia Neurons Organ Pathway interactions Patients Pattern Pharmacology Phenotype Play Post-Translational Protein Processing Refractory Disease Regulatory Element Relapse Research Role Seminal Shapes Skin Cancer Survival Rate Testing The Cancer Genome Atlas Therapeutic Time Toxic effect Transcriptional Activation Transposase United States Up-Regulation Variant WNT Signaling Pathway Writing XCL1 gene Zinc Fingers chromatin immunoprecipitation chromatin remodeling cofactor epigenome falls functional genomics gain of function gene repression knock-down loss of function lymph nodes melanocyte melanoma member migration mutant new therapeutic target novel therapeutic intervention overexpression p38 Mitogen Activated Protein Kinase patient subsets programs promoter recruit relapse patients targeted treatment transcription factor transcriptome sequencing transcriptomics tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Melanoma is the most aggressive form of skin cancer with rising incidence. Despite significant advances, available therapies are effective only in distinct subsets of patients where relapse, treatment-refractory disease, and/or significant toxicities commonly occur. It has become increasingly evident that epigenetic alterations that lead to aberrant gene expression programs play an integral role in melanoma initiation and development. Repressor Element-1 (RE-1) Silencing Transcription (REST), a zinc ﬁnger transcription factor (TF), has been implicated in a diverse subset of cancers as pro-proliferative in neural tumors and anti-proliferative in non-neural tumors. REST binds DNA in a sequence-specific manner at RE1 motifs and primarily functions to repress neuronal gene transcription in non-neuronal cells. REST-mediated gene repression is achieved by the recruitment of several chromatin modifying complexes to DNA that erase active histone marks and write repressive marks. Relevant to my proposal, TCGA data indicates that REST is overexpressed in metastatic melanoma compared to primary melanoma. Yet to date, there are no studies that have explored REST in regulating aberrant gene expression programs in melanoma. I found that REST loss-of-function impairs melanoma proliferation by inducing cell cycle arrest and subsequent apoptosis. RNA-sequencing analysis upon REST knockdown revealed that REST regulates key melanoma survival genes, enriched in pathways related to Cadherin, p38, and Wnt Signaling. Together, my phenotypic and transcriptomic analysis of REST depletion demonstrated, for the first time, that melanoma cells are dependent on REST. In this proposal, I seek to continue to test my hypothesis that through the modulation of the epigenetic landscape, REST regulates pro-tumorigenic transcriptional programs in melanoma, utilizing a combination of functional and genomic approaches. I expect my findings to open avenues for investigation into the molecular mechanisms and cellular functions of REST and ultimately, to present a novel therapeutic strategy for melanoma patients.

项目概要黑色素瘤是最具侵袭性的皮肤癌，尽管取得了重大进展，但其发病率仍在不断上升。现有的疗法仅对复发、难治性疾病、和/或显着的毒性经常发生，这一点已经变得越来越明显。导致异常的基因表达程序在黑色素瘤的发生和发展中发挥着不可或缺的作用。阻遏元件 1 (RE-1) 沉默转录 (REST) 是一种锌指转录因子 (TF)，已被涉及多种癌症亚型，如神经肿瘤中的促增殖作用和非神经肿瘤中的抗增殖作用 REST 在 RE1 基序上以序列特异性方式结合 DNA，主要起到抑制作用。非神经元细胞中的神经元基因转录是通过 REST 介导的基因抑制实现的。将几种染色质修饰复合物招募到 DNA 中，擦除活性组蛋白标记并写入与我的建议相关的是，TCGA 数据表明 REST 在转移性肿瘤中过度表达。迄今为止，还没有研究探讨黑色素瘤与原发性黑色素瘤的 REST 治疗效果。我发现 REST 功能丧失会损害黑色素瘤中的异常基因表达程序。通过诱导细胞周期停滞和随后的细胞凋亡来进行黑色素瘤增殖。 REST 敲除揭示了 REST 调节关键的黑色素瘤存活基因，这些基因富含与钙粘蛋白、p38 和 Wnt 信号传导。我对 REST 耗竭的表型和转录组学分析。首次证明黑色素瘤细胞依赖于 REST 在这项提案中，我寻求继续下去。为了检验我的假设，即通过调节表观遗传景观，REST 可以调节促肿瘤发生我期望利用功能和基因组方法的组合来治疗黑色素瘤。我的发现为研究 REST 的分子机制和细胞功能开辟了途径最终，为黑色素瘤患者提出一种新的治疗策略。