BRG1 promotes survival of UV-irradiated melanoma cells by cooperating with MITF to activate the melanoma inhibitor of apoptosis gene

• Published in: Pigment cell and melanoma research Vol. 26; no. 3; pp. 377 - 391
• Main Authors: Saladi, Srinivas V., Wong, Philip G., Trivedi, Archit R., Marathe, Himangi G., Keenen, Bridget, Aras, Shweta, Liew, Zi-Qi, Setaluri, Vijayasaradhi, de la Serna, Ivana L.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-05-2013; Wiley Subscription Services, Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Cell Line, Tumor; Cell Survival - radiation effects; Cells; Chromatin - metabolism; chromatin remodeling; Cytoprotection - radiation effects; DNA Helicases - metabolism; Gene expression; Gene Expression Regulation, Neoplastic - radiation effects; Histones - metabolism; Humans; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Melanoma; Melanoma - genetics; Melanoma - pathology; Mice; Microphthalmia-Associated Transcription Factor - metabolism; MITF; ML-IAP; Models, Biological; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Proteins - metabolism; Original; Promoter Regions, Genetic - genetics; Proteins; SWI/SNF enzymes; Transcription Factors - metabolism; Transcription, Genetic - radiation effects; ultraviolet radiation; Ultraviolet Rays
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12088

Summary
Microphthalmia‐associated transcription factor (MITF) is a survival factor in melanocytes and melanoma cells. MITF regulates expression of antiapoptotic genes and promotes lineage‐specific survival in response to ultraviolet (UV) radiation and to chemotherapeutics. SWI/SNF chromatin‐remodeling enzymes interact with MITF to regulate MITF target gene expression. We determined that the catalytic subunit, BRG1, of the SWI/SNF complex protects melanoma cells against UV‐induced death. BRG1 prevents apoptosis in UV‐irradiated melanoma cells by activating expression of the melanoma inhibitor of apoptosis (ML‐IAP). Down‐regulation of ML‐IAP compromises BRG1‐mediated survival of melanoma cells in response to UV radiation. BRG1 regulates ML‐IAP expression by cooperating with MITF to promote transcriptionally permissive chromatin structure on the ML‐IAP promoter. The alternative catalytic subunit, BRM, and the BRG1‐associated factor, BAF180, were found to be dispensable for elevated expression of ML‐IAP in melanoma cells. Thus, we illuminate a lineage‐specific mechanism by which a specific SWI/SNF subunit, BRG1, modulates the cellular response to DNA damage by regulating an antiapoptotic gene and implicate this subunit of the SWI/SNF complex in mediating the prosurvival function of MITF.