Molecular mechanism of oncogenic programming by histone demethylase GASC1

组蛋白去甲基化酶GASC1致癌编程的分子机制

基本信息

批准号：
8755828
负责人：
Zeng-Quan Yang
金额：
$ 16.53万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-09 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8755828
关键词：
9p24 Affect Animal Model Architecture Binding Biochemical Biological Assay Biological Process Breast Breast Cancer Cell C-terminal Catalytic Domain Cell model Chromatin Development Disease Enzymes Epigenetic Process Epithelial Event Family Foundations Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genomics Goals Histone H3 Histones Human In Vitro Lead Lysine MCF10A cells Malignant Neoplasms Malignant neoplasm of esophagus Mammary gland Mediating Methylation Modeling Molecular N-terminal Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Phenotype Plants Play Promoter Regions Proteins Public Health Recruitment Activity Recurrence Regulation Research Role Sentinel Signal Pathway Site Skp2 Proteins Specificity Squamous cell carcinoma Testing Therapeutic Translating Ubiquitination Work Xenograft procedure aggressive therapy base breast tumorigenesis cancer cell cancer therapy demethylation design enzyme activity histone modification homeodomain improved in vivo insight malignant breast neoplasm member new therapeutic target novel overexpression programs public health relevance tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this application is to elucidate the fundamental mechanism by which dysregulation of the histone demethylase, GASC1 (Gene Amplified in Squamous Cell Carcinoma 1, also known as JMJD2C and KDM4C), contributes to tumorigenesis, and to lay a foundation for the development of this protein as a new therapeutic target against breast cancer. The GASC1 gene was originally cloned from an amplified region at 9p24 in esophageal cancer cells. Later studies demonstrated that GASC1 is amplified in approximately 15% of breast cancers with overexpression more prevalent in aggressive, basal-type breast cancer. The GASC1 protein is a key member of histone demethylases that play an essential role in regulating chromatin architecture and gene expression; and is implicated in tumorigenesis. GASC1 mainly catalyzes demethylation of tri- and di-methylated forms of histone H3 lysine 9 (H3K9me3/me2) epigenetic repressive marks. However, the molecular mechanisms by which GASC1-dependent chromatin regulation translates to oncogenicity and cancer progression remain poorly understood. Intriguing preliminary evidence indicated that GASC1 is significantly enriched at target gene promoter regions, and that recruitment of GASC1 to specific genomic loci requires the GASC1 Tudor and Plant Homeo Domains (PHD). Studies indicate that the Tudor and PHD domains have the potential to bind H3K4me3 active marks at promoter regions. Importantly, we demonstrated that GASC1 target genes are involved in multiple signaling pathways and biological processes, including critical genes such as the S-phase kinase-associated protein 2 (SKP2) which participates in ubiquitination. The central hypothesis of this application is that GASC1 is recruited to gene promoter regions containing H3K4me3 active marks via its histone-binding domains, and the subsequent demethylation of H3K9me3/me2 repressive marks induces the transcription of a set of key ubiquitination pathway genes that ultimately promote tumorigenesis. Based on this hypothesis, strategies that selectively alter the GASC1 histone recruitment hold great promise as targeted therapies for aggressive, GASC1-amplified breast and esophageal cancers. In this application, two specific aims will be pursued. In Aim 1, we will elucidate the molecular mechanism and structural details of GASC1 that mediate its recruitment to promoter regions of target genes. In Aim 2, we will determine how GASC1 impacts the histone methylation status and expression of target genes responsible for mediating GASC1's role in breast tumorigenesis in vitro and in xenograft animal models. Significantly, the proposed research will fundamentally increase our understanding of the mechanisms by which GASC1 is recruited to genomic loci and how genetic amplification of GASC1 alters epigenetic programming and triggers downstream oncogenic pathways in cancer. These aspects have translational implications in the development of GASC1 mechanism-based therapies to target a wide range of cancers, particularly GASC1-amplified basal breast cancer.

描述（由申请人提供）：该应用的长期目标是阐明基本机制，通过这种机制，组蛋白脱甲基酶的失调，GASC1（基因在鳞状细胞癌1中放大基因，也称为JMJD2C和KDM4C），也称为肿瘤的基础，为乳腺癌造成了癌症的基础。 GASC1基因最初是从食管癌细胞中9p24的扩增区域克隆的。后来的研究表明，在大约15％的乳腺癌中，GASC1在侵略性的基础型乳腺癌中更为普遍。 GASC1蛋白是组蛋白脱甲基酶的关键成员，在调节染色质结构和基因表达中起着至关重要的作用。并与肿瘤发生有关。 GASC1主要催化组蛋白H3赖氨酸9（H3K9ME3/ME2）的三甲基化形式的脱甲基化。然而，依赖GASC1的染色质调节的分子机制转化为致癌性和癌症进展仍然很少了解。有趣的初步证据表明，GASC1在靶基因启动子区域显着富集，并且将GASC1募集到特定的基因组基因局需要需要GASC1 Tudor和Plant Homeo域（PHD）。研究表明，都铎和PHD结构域具有结合启动子区域H3K4ME3活性标记的潜力。重要的是，我们证明GASC1靶基因参与了多种信号通路和生物过程，包括参与泛素化的关键基因，例如与S期激酶相关的蛋白2（SKP2）。该应用的核心假设是，GASC1通过其组蛋白结合域募集到含有H3K4ME3活动标记的基因启动子区域，随后H3K9ME3/ME2抑制标记的脱甲基化诱导了一组关键的泛液途径基因的转录，最终促进了TumorigeNesis。基于这一假设，选择性改变GASC1组蛋白募集的策略是对攻击性，GASC1扩增的乳腺癌和食管癌的有针对性疗法的巨大希望。在此应用程序中，将追求两个具体目标。在AIM 1中，我们将阐明GASC1的分子机制和结构细节，这些机制介导了其募集到靶基因的启动子区域。在AIM 2中，我们将确定GASC1如何影响靶基因的组蛋白甲基化状态和表达，负责介导GASC1在体外和异种移植动物模型中介导GASC1在乳腺肿瘤中的作用。值得注意的是，拟议的研究将从根本上提高我们对GASC1被募集到基因组基因座的机制的理解，以及GASC1的遗传扩增如何改变表观遗传学编程，并在癌症中触发下游致癌途径。这些方面对基于GASC1机制的疗法的发展具有转化的意义，以针对广泛的癌症，尤其是GASC1扩增的基底乳腺癌。