Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

By Jakob Lovén, Heather A. Hoke, Charles Y. Lin, Ashley Lau, David A. Orlando, C. Vakoc, James E. Bradner, Tong Ihn Lee, Richard A. Young. Cell, 2013

2,748 citations recorded by the source corpus.

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.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/185a143749f52b86bbe8b48a90e10e9b0d7d3ebb

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Citations in the corpus

The mechanisms behind the therapeutic activity of BET bromodomain inhibition (2014, background): “These elements have been termed ‘‘super-enhancers’’ and are remarkable for the level and the span of Brd4 occupancy, which can extend across tens of kilobases (Lovén et al., 2013; Whyte et al., 2013).”
PEDLA: predicting enhancers with a deep learning-based algorithmic framework (2016, background): “Genetic variation or disruption in enhancers is closely associated with diseases and cancers (17,18).”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Studies of cohesin dynamics upon BRD4 inhibition with JQ1 led to a twofold decrease in cohesin occupancy at super-enhancer sites and decreased oncogene expression (102, 103).”
Transcriptional Addiction in Cancer (2017, neutral): “…TFs acquire especially large SEs, with exceptionally high densities of enhancer factors, and this may further contribute to the exceptional vulnerability of SEdriven oncogenic TFs seen with inhibition of BRD4 (Bhagwat et al., 2016; Chapuy et al., 2013; Loven et al., 2013; Shi and Vakoc, 2014).”
An Oncogenic Super-Enhancer Formed Through Somatic Mutation of a Noncoding Intergenic Element (2014, background): “Drugs that target key components of the transcriptional machinery, such as BRD4 and CDK7 (12, 13, 17), have recently been shown to preferentially target tumor-specific super-enhancers, which provides a novel strategy to capitalize on these abnormalities for improved cancer therapy.”
Mediator and RNA polymerase II clusters associate in transcription-dependent condensates (2018, background): “called super-enhancers (SEs) and that some are disrupted by loss of the BET bromodomain protein BRD4, which is a cofactor associated with Mediator (18, 19).”
A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. (2014, methodology): “These observations suggest the presence of an active, rearranged superenhancer in inv(3)/ t(3;3) leukemia samples, as was previously observed for MYCrearrangements in multiple myeloma (Lovén et al., 2013).”
Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants (2013, background): “While this manuscript was in preparation, two reports (30, 31) described the presence of large enhancers in mouse cells and human cancer cell lines associated with highly expressed cell identity genes and densely occupied by the Mediator coactivator complex.”
Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II, and Pol III (2020, neutral): “transcription [60, 61].”