Abstract 2245: Mechanism of replicative senescence induced by SNF5 loss

Abstract

Abstract Cellular senescence was initially described as the phenomenon by which normal diploid cells cease to divide after reaching the Hayflick limit. However, with the identification of replicative senescence, other inducers of this process have appeared in the literature including oncogene induced senescence (OIS). Of interest, different oncogenes can initiate OIS through alternative pathways e.g. HRAS (G12V) and BRAF (V600E) that effect senescence through p16 dependent and p16 independent pathways, respectively. Alternatively, loss of tumor suppressor gene function can also induce senescence. In malignant rhabdoid tumors (MRTs), SNF5 behaves as a tumor suppressor and its re-expression in MRT cell lines results in growth arrest via the RB pathway. Paradoxically, when we knocked out SNF5 in normal human fibroblasts (NHF-1), we also observed senescence. We therefore hypothesize that perturbation of the SWI/SNF complex (e.g. knocking down SNF5) results in cellular senescence in most normal tissues. This suggests an epigenetic mechanism of senescence occurring through a p16 independent pathway, as previous publications have demonstrated a critical role for SNF5 in p16 expression. Additionally, in BRAF induced senescence, changes in levels of CD44, phospho-MEK1/2, and p16 are observed. However, we do not find these changes during SNF5 loss. Our findings suggest a relationship between SWI/SNF's chromatin remodeling activity and the regulation of cellular senescence. Importantly, our studies will identify the key signaling pathways that allow MRTs to escape cellular senescence after SNF5 loss. These results will further elucidate the role of SNF5 loss in MRT development and provide new targets for clinical intervention. Acknowledgement: We thank the members of the Weissman lab for their help, advice, and support and R01CA91048 (B.E.W.) , T32ES007126 (D.W.), UNC Dissertation Completion Fellowship (D.W.) for financial support. Citation Format: Darmood Wei, HoYoon Chung, Dennis A. Simpson, William K. Kaufmann, Bernard E. Weissman. Mechanism of replicative senescence induced by SNF5 loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2245. doi:10.1158/1538-7445.AM2014-2245