Abstract
Loss of the compensatory chromatin remodeler EP400 sensitizes cancer cells to SWI/SNF inhibition.
Major Finding: Loss of the compensatory chromatin remodeler EP400 sensitizes cancer cells to SWI/SNF inhibition.
Concept: EP400 rapidly restores chromatin accessibility upon SWI/SNF inhibition at many gene promoters.
Impact: This study suggests the potential of targeting EP400 to enhance the efficacy of SWI/SNF inhibitors.
Mammalian SWI/SNF chromatin remodeling complexes control gene expression through ATP-dependent nucleosome sliding, and mutations in SWI/SNF complex subunits are frequently observed in human cancer. Despite the oncogenic impact of aberrant SWI/SNF activity, the direct targets of SWI/SNF-dependent nucleosome remodeling are not well understood. To profile the effects of SWI/SNF perturbation, Martin, Ablondi, and colleagues treated mouse embryonic stem cells (mESC) with BRM014, a fast-acting pharmacologic inhibitor of the BRG1 and BRM ATPase subunits of SWI/SNF, and examined the chromatin accessibility and transcriptional consequence of acute inhibition. A global reduction in chromatin accessibility and transcriptional activity was evident at active promoters and enhancers as early as 2 hours post–BRM014 treatment, and enhancer accessibility remained repressed during prolonged SWI/SNF inhibition. In contrast, while a subset of promoters remained repressed, promoter accessibility was restored at the majority of affected loci within 4 hours of BRM014 treatment, suggesting a compensatory mechanism to maintain gene activity. Comparison of promoters that compensated for loss of SWI/SNF activity with promoters that were sensitive to SWI/SNF inhibition revealed that the latter class of SWI/SNF-dependent promoters exhibited low average chromatin accessibility, low RNA expression, and enhancer-like chromatin features such as increased monomethylation of histone 3 at lysine 4 (H3K4me1). Extension of these findings to cancer cell lines of different tissues demonstrated that H3K4me1 enrichment and low chromatin accessibility at promoters were predictive of genes that were sensitive to SWI/SNF inhibition. Analysis of chromatin remodeler localization across clusters of promoters with differential SWI/SNF sensitivity suggested that the EP400/TIP60 chromatin remodeling complex functionally compensated for loss of SWI/SNF activity at many loci. Moreover, genetic perturbation of EP400 in the context of BRM014 treatment prevented the recovery of chromatin accessibility and enhanced the cell viability defects of SWI/SNF inhibition. Together, these findings systematically identify SWI/SNF-regulated enhancers and promoters and uncover a synthetic lethal relationship between SWI/SNF and EP400/TIP60 complex function.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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