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Role of GAS41 in human cancer

GAS41 在人类癌症中的作用

基本信息

批准号：
9238751
负责人：
Xiaobing Shi
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
2016-03-07 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238751
关键词：
AF-9 protein Acetylation Antineoplastic Agents Binding Biochemical Biological Assay Biological Process Bromodomain Cancer Cell Growth Cancer Patient Cancer cell line Cell Proliferation Cells ChIP-seq Childhood Chromatin Chromatin Remodeling Factor Complex Deposition Epigenetic Process Evolution GAS41 gene Gene Activation Gene Expression Genetic Transcription Genomic Instability Genomics Glioblastoma Glioma Histone Acetylation Histone H2A Histone H3 Histones Human In Vitro Instruction Link Lysine MLLT3 gene Malignant Neoplasms Malignant neoplasm of lung Mixed-Lineage Leukemia Modification Molecular Mus Mutation Oncogenes Oncogenic Pathogenesis Pathway interactions Play Proteins Reader Reading Recruitment Activity Regulation Role Tertiary Protein Structure Testing The Cancer Genome Atlas Therapeutic Variant Xenograft procedure actionable mutation base cancer genome cancer genomics cancer therapy experimental study gene translocation genomic data in vivo inhibitor/antagonist leukemia lung tumorigenesis malignant breast neoplasm mouse model new therapeutic target outcome forecast preference protein complex public health relevance sarcoma therapeutic target transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant). In the past few years, the cancer genome projects have identified frequent alterations in a large number of chromatin regulatory factors in cancers; however, the roles of these alterations in the pathogenesis of human cancers remain largely unknown. The Glioma Amplified Sequence 41 (Gas41) gene is frequently amplified in a number of human cancers, including glioblastoma, sarcoma, breast, and lung cancer, but the role of Gas41 in cancer is unknown. At the molecular level, Gas41 is associated with the SRCAP and Tip60/p400 complexes, which control the exchange of the canonical histone H2A in the chromatin for H2A.Z, a variant histone that is normally required for gene expression. Although the role of SRCAP and Tip60/p400 in H2A.Z deposition is relatively well characterized, the actual function of Gas41 within these complexes is largely unknown. In our preliminary studies, we found that the Gas41 protein can specifically recognize histone acetylation, a type of modification on histone proteins that is required for gene activation. This finding suggests that Gas41 may function as a "reader" of histone acetylation and that this reading activity is important for recruiting the SRCAP and Tip60/p400 complexes to chromatin, promoting H2A.Z deposition and gene activation. In this study, we will combine in vitro biochemical approaches with in vivo genomic and functional assays to determine whether Gas41 is required for the function of the SRCAP and Tip60/p400 complexes on chromatin, and whether amplification of Gas41 contributes to the pathogenesis of lung cancer. As Gas41 is amplified in many types of human cancer, findings from this study will be instructive for our understanding of the role of Gas41 in other types of human cancer, and will support the idea that the Gas41 YEATS domain is a potential new therapeutic target for cancer treatment.

描述（由申请人提供）。过去几年，癌症基因组计划发现癌症中大量染色质调控因子频繁发生改变；然而，这些改变在人类癌症发病机制中的作用仍然很大程度上未知。胶质瘤扩增序列 41 (Gas41) 基因经常在多种人类癌症中扩增，包括胶质母细胞瘤、肉瘤、乳腺癌和肺癌，但 Gas41 在癌症中的作用尚不清楚。在分子水平上，Gas41 与 SRCAP 和 Tip60/p400 复合体相关，后者控制染色质中典型组蛋白 H2A 与 H2A.Z 的交换，H2A.Z 是基因表达通常所需的变体组蛋白。尽管 SRCAP 和 Tip60/p400 在 H2A.Z 沉积中的作用已相对较好地表征，但 Gas41 在这些复合物中的实际功能很大程度上未知。在我们的初步研究中，我们发现 Gas41 蛋白可以特异性识别组蛋白乙酰化，组蛋白乙酰化是基因激活所需的一种组蛋白修饰。这一发现表明，Gas41 可能充当组蛋白乙酰化的“读取器”，并且这种读取活动对于将 SRCAP 和 Tip60/p400 复合物招募到染色质、促进 H2A.Z 沉积和基因激活非常重要。在本研究中，我们将体外生化方法与体内基因组和功能测定相结合，以确定 Gas41 是否是染色质上 SRCAP 和 Tip60/p400 复合物的功能所必需的，以及 Gas41 的扩增是否有助于肺癌的发病机制。由于 Gas41 在许多类型的人类癌症中被扩增，这项研究的结果将有助于我们了解 Gas41 在其他类型的人类癌症中的作用，并将支持 Gas41 YEATS 结构域是癌症治疗的潜在新治疗靶点的观点。