Role of GAS41 in human cancer

 描述(由申请人提供)。在过去的几年里，癌症基因组计划已经发现了癌症中大量染色质调节因子的频繁变化；然而，这些变化在人类癌症发病机制中的作用在很大程度上仍不清楚。胶质瘤扩增序列41(Gas41)基因在许多人类癌症中经常被扩增，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，这两个复合体控制着染色质中典型的组蛋白H_2A与H_2A的交换，H_2A是一种变异组蛋白，通常是基因表达所必需的。虽然SRCAP和Tip60/P400在H2A.Z沉积中的作用相对较好，但Gas41在这些复合体中的实际功能在很大程度上是未知的。在我们的初步研究中，我们发现Gas41蛋白可以特异性地识别组蛋白乙酰化，这是基因激活所需的一种组蛋白修饰。这一发现表明，Gas41可能是组蛋白乙酰化的“阅读器”，这种阅读活性对于将SRCAP和Tip60/P400复合体招募到染色质，促进H2A.Z沉积和基因激活是重要的。在这项研究中，我们将结合体外生化方法与体内基因组和功能分析来确定Gas41是否是SRCAP和Tip60/P400复合体在染色质上发挥功能所必需的，以及Gas41的扩增是否参与肺癌的发病。由于Gas41在许多类型的人类癌症中扩增，本研究的发现将有助于我们理解Gas41在其他类型人类癌症中的作用，并将支持Gas41 Yeats结构域是癌症治疗的潜在新靶点的观点。

 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.