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Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets

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Abstract

Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as “super-enhancers” drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.

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Acknowledgements

The authors would like to thank Elise Wright for her help in illustrating the figures.

Funding

This work was funded by the National Institutes of Health R01 CA236356, R01 CA268183, R01 CA281024 to W.X. and the National Cancer Institute NRSA award T32 CA009135 to M.B.

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, 1111 Highland Ave, Madison, WI, 53705, USA

    Megan Bacabac & Wei Xu

  2. School of Medicine and Public Health, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA

    Megan Bacabac & Wei Xu

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M.B. and W.X. conceived the idea for this manuscript. M.B. performed the literature search and drafted the manuscript. W.X. critically revised the manuscript.

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Correspondence to Wei Xu.

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Bacabac, M., Xu, W. Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets. Cancer Metastasis Rev 42, 471–480 (2023). https://doi.org/10.1007/s10555-023-10103-4

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