. 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.

Public Health Relevance

The cancer genome projects have identified frequent alterations in a large number of epigenetic regulators in human cancer. However, it remains largely unknown whether these alterations are 'drivers' of human cancer. This proposal aims to elucidate the functions and mechanisms of Glioma Amplified Sequence 41 (GAS41), an oncogene that is frequently amplified in human cancers, in linking histone acetylation recognition to tumorigenesis of lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Johnson, Ronald L
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Van Andel Research Institute
Grand Rapids
United States
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