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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Selective inhibition of tumor oncogenes by disruption of super-enhancers
Jakob Lovén1, Heather A Hoke, Charles Y Lin
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Abstract:
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.
Insights
Inhibition of BRD4 selectively targets the MYC oncogene in multiple myeloma by affecting super-enhancers. This finding offers new therapeutic strategies for various cancers targeting super-enhancer components.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Chromatin regulators are key cancer therapy targets.
- Understanding gene-specific effects of inhibiting these regulators is crucial.
Purpose of the Study:
- Investigate how BRD4 inhibition selectively affects the MYC oncogene in multiple myeloma (MM).
- Explore the role of super-enhancers in mediating these effects.
Main Methods:
- Analyzing BRD4 and Mediator co-occupancy at enhancers and super-enhancers.
- Treating MM cells with BET-bromodomain inhibitor JQ1.
- Assessing transcriptional changes and BRD4 localization.
Main Results:
- BRD4 and Mediator co-occupy thousands of enhancers, including super-enhancers for MM-specific genes like MYC.
- JQ1 treatment caused preferential loss of BRD4 at super-enhancers.
- This led to transcription defects impacting super-enhancer-driven genes, notably MYC.
Conclusions:
- BRD4 inhibition selectively impacts MYC in MM via super-enhancers.
- Super-enhancers are critical for oncogenic drivers in various cancers.
- Targeting super-enhancer components presents a promising therapeutic avenue for diverse tumor types.
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