Role of GAS41 in human cancer

 描述（由申请人提供）。在过去的几年中，癌症基因组计划已经确定了大量的染色质调节因子在癌症中的频繁改变;然而，这些改变在人类癌症发病机制中的作用在很大程度上仍然未知。胶质瘤扩增序列41（Gas 41）基因在许多人类癌症中经常扩增，包括胶质母细胞瘤、肉瘤、乳腺癌和肺癌，但Gas 41在癌症中的作用尚不清楚。在分子水平上，Gas 41与SRCAP和Tip 60/p400复合物相关，其控制染色质中的典型组蛋白H2 A与H2A.Z的交换，H2A.Z是基因表达通常所需的变体组蛋白。虽然SRCAP和Tip 60/p400在H2A.Z沉积中的作用相对较好地表征，但Gas 41在这些复合物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Gas 41蛋白可以特异性识别组蛋白乙酰化，这是一种基因激活所需的组蛋白修饰。这一发现表明Gas 41可能作为组蛋白乙酰化的“阅读器”发挥作用，并且这种阅读活性对于将SRCAP和Tip 60/p400复合物募集到染色质、促进H2A.Z沉积和基因活化是重要的。在这项研究中，我们将结合联合收割机在体外生物化学的方法，在体内基因组和功能检测，以确定是否Gas 41所需的SRCAP和Tip 60/p400复合物的染色质上的功能，以及是否Gas 41的扩增有助于肺癌的发病机制。由于Gas 41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Gas 41在其他类型的人类癌症中的作用，并将支持Gas 41 YEATS结构域是癌症治疗的潜在新治疗靶点的想法。

 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.