Abstract 363: Role of the SAGA histone acetylation module in lung cancer

Abstract Lung cancer causes the highest mortality in cancer-related deaths. Definition of novel molecular targets is needed since these cancers often become resistant to existing therapies. Epigenetic modifications may provide such targets. Recent reports suggest that the histone acetyltransferase (HAT) module within the transcriptional coactivator SAGA complex plays a role in cancer, creating a new link between epigenetic regulators and this disease. We are working to define the role of the SAGA HAT protein GCN5 in the regulation and function of oncogenes in lung cancers. Since our prior work indicates that GCN5 serves as a coactivator for MYC target genes, we hypothesize that inhibition of GCN5 will reduce lung oncogenesis by suppressing MYC functions. We also propose that inhibition of GCN5 will reduce lung cancer formation and progression in mouse models of lung cancer. Our preliminary data indicate that both GCN5 and MYC expression levels are upregulated and positively associated in mouse and human lung cancers. Both proteins are also associated with MYC target genes in lung cancer tissues. Inhibition of the GCN5 active site or bromodomain significantly (p < 0.05) reduces cell proliferation compared to normal lung epithelium cells. Studies investigating how GCN5 inhibition affects other lung cancer phenotypes are underway. Specific genes and pathways affected by GCN5 loss will be determined using RNA-Seq and RPPA assays to identify mechanisms behind observed phenotypes. In addition, we will determine whether knockout of Gcn5 reduces lung formation and progression in the KrasLA2 lung cancer mouse model. Our ongoing studies will determine whether targeting GCN5 represses multiple oncogenic pathways in cancer and whether it inhibits oncoproteins difficult to directly target, such as MYC. We expect that our findings will highlight the importance of epigenetic regulators in carcinogenesis and extend beyond our current research focus to other cancer types. Citation Format: Lisa Maria Mustachio, Jason Roszik, Sharon YR Dent. Role of the SAGA histone acetylation module in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 363.