Abstract LB-18: BRG1 promotes melanoma survival in response to DNA damage

Abstract

Abstract The objective of this study is to elucidate the mechanisms by which BRG1 promotes melanoma survival in response to DNA damage. Cutaneous malignant melanoma, is an aggressive malignancy that arises from the transformation of epidermal melanocytes and is notoriously chemoresistant. Exposure to ultraviolet radiation (UVR) from sunlight is the most critical environmental agent involved in melanoma genesis. Melanocytes protect surrounding skin cells from UVR damage and because of this protective role, melanocytes have evolved to be particularly resistant to apoptosis when exposed to UVR. The lineage specific mechanisms that prevent cell death of melanocytes exposed to UVR are thought to contribute to melanoma chemoresistance. Microphthalmia-associated transcription factor (MITF), a master regulator of differentiation in melanocytes, is a lineage addiction oncogene in melanoma. We previously demonstrated that MITF interacts with the SWI/SNF complex to activate MITF target gene expression. SWI/SNF enzymes are multi-subunit ATP dependent chromatin remodeling complexes that regulate gene expression and promote DNA repair. Several of the subunits act as tumor suppressors and are mutated or absent in many forms of cancer. Re-expression of SWI/SNF subunits in cancer cell lines deficient in a particular subunit often results in cell cycle arrest and reversion of the tumorigenic phenotype. However, re-expression of the SWI/SNF subunit, BRG1, in BRG1 deficient melanoma cells increases survival to cisplatin and to UVR exposure. Furthermore, we have found that BRG1 is highly expressed in melanoma tumors and its expression increases during late stages of melanoma, potentially contributing to the chemoresistance typical of advanced melanoma. Our hypothesis is that BRG1promotes lineage specific activation of anti-apoptotic pathways through interactions with MITF. Data indicate that BRG1and MITF expression are closely correlated with expression of the melanoma inhibitor of apoptosis (ML-IAP) gene and that BRG1 promotes dramatic chromatin modifications on the ML-IAP regulatory region, strongly activating expression of this MITF target gene. ML-IAP is a potent inhibitor of apoptosis, which is highly expressed in melanomas and contributes to the survival of melanoma cells exposed to DNA damaging agents. Our current studies are focused on the mechanisms by which BRG1 activates ML-IAP expression and on elucidating the role of ML-IAP in mediating BRG1 induced survival of melanoma cells exposed to UVR. We expect that down-regulation of ML-IAP will significantly compromise BRG1 mediated survival of melanoma cells exposed to UVR. The results from these studies should illuminate a lineage specific mechanism by which BRG1 promotes survival of melanoma cells exposed to a DNA damaging agent and implicate BRG1 as a target for epigenetic based therapeutics to treat this highly resistant malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-18. doi:10.1158/1538-7445.AM2011-LB-18