Heterogeneous SWI/SNF chromatin remodeling complexes promote expression of microphthalmia-associated transcription factor target genes in melanoma

Abstract

The microphthalmia-associated transcription factor (MITF) promotes melanocyte differentiation and cell cycle arrest. Paradoxically, MITF also promotes melanoma survival and proliferation, acting like a lineage survival oncogene. Thus, it is critically important to understand the mechanisms that regulate MITF activity in melanoma cells. SWI/SNF chromatin remodeling enzymes are multiprotein complexes composed of one of two related ATPases, BRG1 or BRM, and 9-12 associated factors (BAFs). We previously determined that BRG1 interacts with MITF to promote melanocyte differentiation. However, it was unclear whether SWI/SNF enzymes regulate the expression of different classes of MITF target genes in melanoma. In this study, we characterized SWI/SNF subunit expression in melanoma cells and observed down-regulation of BRG1 or BRM, but not concomitant loss of both ATPases. Re-introduction of BRG1 in BRG1 deficient SK-MEL5 cells enhanced expression of differentiation specific MITF target genes and resistance to cisplatin. Down-regulation of the single ATPase, BRM, in SK-MEL5 cells inhibited expression of both differentiation specific and pro-proliferative MITF target genes and inhibited tumorigenicity in vitro. Our data suggest that heterogeneous SWI/SNF complexes composed of either the BRG1 or BRM subunit promote expression of distinct and overlapping MITF target genes and that at least one ATPase is required for melanoma tumorigenicity.

Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation

“…In six of the eight cell lines, mutations were biallelic (Table 1). In SK-MEL-5, only one allele has been found mutated, but this cell line has previously been shown to lack SMARCA4 expression, suggesting complete loss of function (29). In HEC1A, only one allele was mutated, and this cell line has previously been shown to express the SMARCA4 protein (30).…”

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

“…These factors include the Y-box binding protein-1, CCAAT-binding transcription factor 2, activating transcription factor 4, zincfinger factor 143, the nuclear transcription factor-B, the microphthalmia-associated transcription factor, the forkhead transcription factor O, and mitochondrial transcription factor A (Torigoe et al, 2005;Lee et al, 2009;Lei and Quelle, 2009;Li et al, 2009;Keenen et al, 2010). Hirano et al (2010) reported that p300/CBP-associated factor (PCAF) was overexpressed in human prostate and epidermal cisplatin-resistant P/CDP6 and HeLa/CP4 cells.…”

Dual roles of lineage restricted transcription factors

“…It was also described that MITF recruits the SWI/SNF complex to the promoters of differentiation-related targets Tyrosinase and TRP1, but not to cell maintenance genes TBX2 and BCL2. 27,28 This mechanism is suggested to drive selective expression of MITF target genes. SWI/SNF complexes are ATP-dependent chromatinremodeling enzymes that alter the position of nucleosomes along the chromosome and, as a consequence, affect promoter accessibility to regulatory factors.…”