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NSD1 Inactivation in Head and Neck Cancer

头颈癌中 NSD1 失活

基本信息

批准号：
9352812
负责人：
Chao Lu
金额：
$ 13.79万
依托单位：
ROCKEFELLER UNIVERSITY
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：
2016-09-14 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352812
关键词：
Area Award Biochemical Biochemical Genetics Biological Markers Biology Calcium Cancer Model Career Mobility ChIP-seq Chemicals Chromatin Coupled DNA DNA Binding DNA Methylation DNA Modification Methylases DNA Sequence Alteration Data Deletion Mutation Developed Countries Developing Countries Development Ectopic Expression Engineering Enzymes Epigenetic Process Exhibits Gene Expression Regulation Genetic Genome Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Histone H3 Histones Homeostasis Knock-out Lysine Malignant Childhood Neoplasm Malignant Epithelial Cell Malignant Neoplasms Mediating Mentors Methionine Methods Methylation Methyltransferase Molecular Mus Mutate Mutation Operative Surgical Procedures Pathogenesis Patient Care Phase Play Radiation Recruitment Activity Recurrence Reporting Research Research Personnel Role Subgroup Technology Testing Tissue Differentiation Tissues Training Translating Tumorigenicity Work cancer genome career development chemotherapy chromatin immunoprecipitation effective therapy epigenomics experimental study genome sequencing genome-wide head and neck cancer patient histone methylation human disease improved in vivo insight keratinocyte keratinocyte differentiation methylome mouse model mutant novel outcome forecast sarcoma transcriptome transcriptome sequencing transcriptomics treatment strategy tumorigenic

项目摘要

PROJECT SUMMARY Increasing evidence has supported a role for chromatin misregulation in the pathogenesis of various human diseases including cancer, although the underlying mechanism remains unclear. Recent tumor genome sequencing efforts have identified inactivating mutations in NSD1, a histone H3 lysine 36 (H3K36)-specific methyltransferase, in 10-15% of head and neck squamous cell carcinomas (HNSCC), the sixth leading cancer worldwide. This study focuses on elucidating the molecular mechanisms by which NSD1 inactivation facilitate HNSCC development and will test the central hypothesis that biochemical and genetic inactivation of NSD1 alters DNA methylome and transcriptome to disrupt squamous tissue differentiation and promote HNSCC initiation in vivo. During the mentored training period, I will characterize the biochemical basis and functional importance of NSD1 inhibition by H3 lysine 36 to methionine (H3K36M) mutation, an oncohistone previously associated with pediatric malignancies and identified in HNSCC through my preliminary studies. I will also profile the impact of NSD1 and H3K36M mutations on the genome-wide distribution of H3K36 methylation and DNA methylation as well as on the transcriptome. During the independent phase of the award period, I propose to investigate the function of NSD1 in squamous tissue differentiation and in vivo suppression of HNSCC. Together the proposed studies will provide novel insights into the pathogenesis of a subset of genetically defined and epigenetically distinct HNSCC that can translate into improved care for patients. They will also serve as a platform for me to obtain trainings in chemical biology, computational epigenomics and mouse models of cancer that will critically contribute to my career development as an independent investigator in the field of cancer epigenetics.

项目摘要越来越多的证据支持染色质失调在各种人类肿瘤的发病机制中的作用。包括癌症在内的疾病，尽管潜在的机制仍不清楚。近期肿瘤基因组测序工作已经确定了NSD 1中的失活突变，NSD 1是组蛋白H3赖氨酸36（H3 K36）特异性的甲基转移酶，10-15%的头颈部鳞状细胞癌（HNSCC），第六大癌症国际吧本研究的重点是阐明NSD 1失活的分子机制， HNSCC的发展，并将测试中心假设，NSD 1的生化和遗传失活改变DNA甲基化组和转录组以破坏鳞状组织分化并促进HNSCC 体内引发。在指导培训期间，我将描述生物化学基础和功能 H3赖氨酸36对蛋氨酸（H3 K36 M）突变NSD 1抑制重要性，与儿童恶性肿瘤相关，并通过我的初步研究在HNSCC中确定。我也会分析NSD 1和H3 K36 M突变对H3 K36甲基化全基因组分布的影响， DNA甲基化以及转录组。在奖励期的独立阶段，我建议研究NSD 1在鳞状组织分化和体内抑制HNSCC中的功能。总之，拟议的研究将提供新的见解的发病机制的一个子集的遗传定义和表观遗传学上不同的HNSCC，可以转化为改善对患者的护理。他们还将作为我获得化学生物学、计算表观基因组学和小鼠癌症模型，这将对我作为一名独立研究者的职业发展做出重要贡献。癌症表观遗传学领域。