Abstract 360: The role of polybromo1 in stress response

Abstract

Abstract Polybromo1 (PBRM1) is mutated in 3.5% of human cancers with the highest incident in renal clear cell carcinoma (40%). PBRM1 is a member of the PBRM1-Brg-Associating Factors (PBAF) chromatin remodeling complex and is characterized by six tandem bromodomains. PBRM1 acts as a tumor suppressor and when deleted along with VHL, the most frequently mutated gene in RCCC, tumors develop in mice. We have previously shown that PBRM1 regulates the expression of genes involved in cell adhesion, apoptosis, and negative cell proliferation in a RCCC cell line. Additionally, we have demonstrated that four of the six bromodomains work together to regulate binding of the complex to chromatin, gene expression, and tumor suppression in RCCC, which correlates with pattern of PBRM1 missense mutations found in RCCC patient tumors. Through this work we identified histone 3 lysine 14 acetylation (H3K14Ac) as the chromatin mark essential for PBRM1 binding. While H3K14Ac is generally found at active promoters, it is also induced at the promoters of stress genes when cells experience stressors such as metabolic stress, osmotic stress, ER stress, or reactive oxygen species (ROS) stress. Knockdown of PBRM1 in normal epithelial cells leads to an increase in proliferation and a partial epithelial to mesenchymal transition (EMT), consistent with low grade ROS. RNA-seq analysis further confirmed a role for PBRM1 in regulating stress response genes. Although loss of PBRM1 increases proliferation in epithelial cells, it also increases cell vulnerability to high levels of ROS. Together this suggests that PBRM1 can be growth promoting or growth inhibiting to cells depending on the cells environment and stress response needs. Citation Format: Elizabeth G. Porter, Emily C. Dykhuizen. The role of polybromo1 in stress response [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 360.