Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Abstract

Summary Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…Under this condition, BRD2 binding was almost completely depleted at a global level (Figure 4(a)). Consistent with previous studies[6,16], we did not observe any global changes in H3K27ac level (Fig. S7A).…”

“…In a complementary analysis, we examined the enrichment of bromodomain proteins BRD2, BRD4, and EP300 at the H4K5acK8ac sites using the publicly available ChIP-seq datasets from the closely related cell types: BRD4 ChIP-seq from SCLC cell line H2171 (GSM1038270) [16] and ENCODE P300 ChIP-seq from NSCLC A549 [25]. We found that promoter- and enhancer-associated H4K5acK8ac regions were enriched for BRD2, BRD4, and EP300 (Fig.…”

“…Additionally, H4 K5 acetylation (H4K5ac) facilitated by histone acetyltransferase p300 (EP300) and disruptor of telomere silencing 1-like (DOT1L) might facilitate the binding of BRD4 to the chromatin [15]. At a genome-wide level, BRD2, BRD3, and BRD4 co-occupy H3K27ac sites at most of the active promoters together with RNA polymerase II and Mediator complex [16–18]. However, it is unclear whether BET proteins have a preferred binding to hyperacetylated histone H4 or H3K27ac in vivo .…”

“…However, it is unclear whether BET proteins have a preferred binding to hyperacetylated histone H4 or H3K27ac in vivo . Furthermore, while genome-wide H3K27ac-enriched sites that overlap highly with BRD2, BRD3, and BRD4 binding sites are not sensitive to a certain concentration of JQ1 [6,16], effects of JQ1 to hyperacetylated histone H4 are not studied at the genome-wide level. The lack of antibody specifically recognizing the hyperacetylated states of histone H4 tail potentially hampers efforts to address this question.…”

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

“…4). Consistent with prior literature, super enhancer (SE) domains were significantly associated with greater transcriptional load 6–9 (Extended Data Fig. 4).…”