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BET domain co-regulators in obesity, inflammation and cancer

Nature Reviews Cancer volume 12, pages 465–477 (2012)Cite this article

Subjects

Key Points

  • Mammalian BET proteins, a class of transcriptional co-regulators that contain dual, mutually related bromodomain motifs and an extraterminal domain, are important in the control of networks of genes; these proteins bind to acetylated lysines in the histones of nucleosomal chromatin, recruit chromatin-modification enzymes to target promoters and function as co-activators or co-repressors of gene expression, depending on the context.

  • New small-molecule inhibitors have recently been developed that disrupt the binding interface between the bromodomain and the acetylated lysine groups; the inhibitors have remarkable potency, selectivity and are well tolerated. They have recently been used as anticancer and anti-inflammatory agents.

  • These developments are important because chromatin was not considered to be a druggable target; as a result of these new drugs, a whole field of new epigenetically targeted therapeutics has become available for investigation.

  • As this field of therapeutics rapidly expands, several features of BET protein function will need to be considered, including possible redundancy among the closely related family members, the selectivity of next-generation agents for specific BET proteins, and possible undesirable consequences of systemic administration without cellular targeting. These side effects might include uncontrolled transcriptional derepression of genes, altered haematopoiesis, immunosuppression or reactivation of latent viruses.

Abstract

The bromodomain is a highly conserved motif of 110 amino acids that is bundled into four anti-parallel α-helices and found in proteins that interact with chromatin, such as transcription factors, histone acetylases and nucleosome remodelling complexes. Bromodomain proteins are chromatin 'readers'; they recruit chromatin-regulating enzymes, including 'writers' and 'erasers' of histone modification, to target promoters and to regulate gene expression. Conventional wisdom held that complexes involved in chromatin dynamics are not 'druggable' targets. However, small molecules that inhibit bromodomain and extraterminal (BET) proteins have been described. We examine these developments and discuss the implications for small molecule epigenetic targeting of chromatin networks in cancer.

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Figure 1: Structure and relationships among bromodomain-containing proteins.
Figure 2: Motif alignment of double bromodomain-containing proteins.
Figure 3: Small-molecule inhibitors of BET proteins.
Figure 4: Model for BET protein co-repression of PPARγ-responsive genes.
Figure 5: BET proteins co-regulate transcriptional networks of transcriptional activation and repression.

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Acknowledgements

This work is supported by grants from the American Cancer Society, Leukaemia and Lymphoma Society and National Institutes of Health. The authors thank J. Bradner, B. Corkey, T. Gilmore, B. Nikolajczyk and M. Obin for useful discussions, and they thank their virology colleagues P. Howley, K. Kaye, D. Margolis, M. Montano and G. Viglianti for generously sharing reagents and ideas.

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  1. Departments of Medicine and Pharmacology, Cancer Research Center, Nutrition Obesity Research Center, Boston University School of Medicine, 72 East Concord Street, K520, Boston, 02118, MA, USA

    Anna C. Belkina & Gerald V. Denis

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Belkina, A., Denis, G. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer 12, 465–477 (2012). https://doi.org/10.1038/nrc3256

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