Abstract
Inhibition of BET protein bromodomains BD1 and BD2 produces unique phenotypes in disease models.
Major Finding: Inhibition of BET protein bromodomains BD1 and BD2 produces unique phenotypes in disease models.
Concept: Inhibition of BD1 but not BD2 restricts cancer growth, but both modulate immunity and inflammation.
Impact: This shows that these domains have distinct roles and that selective targeting may be of interest.
The inhibition of BET proteins, which are epigenetic readers that contain two tandem bromodomains (BD1 and BD2) for chromatin binding and transcription activation, has yielded promising results in preclinical and clinical studies of hematologic and solid cancers. The first-generation BET inhibitors currently under investigation exhibit equal affinity for BD1 and BD2, and little is known about the potentially unique functions of these two bromodomains. To address this knowledge gap, Gilan, Rioja, and colleagues used structure-based design to develop highly selective BD1 and BD2 inhibitors termed iBET-BD1 and iBET-BD2, respectively. Experiments using a variety of human cancer cell lines revealed that iBET-BD1 had similar effects as a pan-BET inhibitor, inhibiting proliferation and resulting in cell-cycle arrest and apoptosis, and in vivo experiments using a mouse model of acute myeloid leukemia showed that iBET-BD1 provided a greater increase in survival than iBET-BD2. According to nascent RNA–sequencing experiments, the transcriptome of iBET-BD1–treated cells resembled that of cells treated with a pan-BET inhibitor, whereas iBET-BD2–treated cells showed little transcriptomic perturbation. Further experiments revealed that BD2 was dispensable for chromatin binding by BET proteins and, hence, maintenance of preexisting transcriptional states; however, BD2 was important for initial binding of BET proteins to chromatin to facilitate induction of gene expression. Additionally, functional in vitro assays showed that, despite not affecting cancer-cell proliferation or survival, BD2 inhibition, like BD1 inhibition, exerted immunomodulatory effects, inhibiting the production of effector cytokines. This along with some prior findings raised the possibility that, although selective BD2 inhibition is not effective in cancer, it may be valuable in some immunoinflammatory diseases. This notion was supported by results from experiments in a rat model of rheumatoid arthritis, a mouse model of psoriasis, and a mouse model of nonalcoholic fatty liver disease. Collectively, these findings establish unique functions for BD1 and BD2 and suggest that current therapeutic strategies based on BET targeting in cancer and immunoinflammatory diseases may be refined by selective targeting of either domain.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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