Bromodomain and Extra Terminal domain (BET) proteins "read" acetyl-lysine in chromatin and are important new epigenetic actors. BET proteins (Brd2, Brd3, Brd4 and Brdt) co-activate cell cycle genes; Brd4 and myc together promote cancer growth. Our 1996 report linking Brd2 expression to human leukemia first demonstrated mammalian BET protein function. The field has grown greatly since then to develop small molecule BET inhibitors, such as I-BET151 and JQ1, which show promise for human cancers. These compounds block BET protein binding, but lack selectivity within the BET family, so that contributions of each family member to transcriptional and cellular outcomes are unresolvable. Overlapping yet discrete roles for individual BET proteins in inflammation and metabolism reveal the need for isoform-selective BET inhibitors as a central challenge. It is also clear that BET proteins transcriptionally co-activate one set of genes but co-repress others. Thus, BET inhibitors can promote transcription: JQ1 effectively reactivates latent HIV virus in infected human T cells, which may offer useful therapy for HIV patients, but pose a safety problem in cancer. Unknown, latent DNA viruses in the human genome might be released unawares in cancer patients. Intriguingly, BET inhibitors could be useful to treat obese, diabetic patients. Genetic ablation of Brd2 activates insulin gene transcription in embryonic stem cells (Figure), suggesting a gene therapy option for diabetes. Furthermore, there are multiple improvements in pancreatic β-cells upon BET inhibition. JQ1 increases insulin secretion and content in cell culture models and human pancreatic islets. But shRNA experiments show that inhibition of Brd2 alone improves fatty acid oxidation; Brd4 is not relevant for this function. Thus, BET protein biology is still underdeveloped; more animal models to test new inhibitors are needed to move the field forward.

BET proteins: Biology beyond cancer

251st National Meeting (2016)

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