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Review
. 2018 May;40(5):e1800007.
doi: 10.1002/bies.201800007. Epub 2018 Mar 30.

BET-ting on Nrf2: How Nrf2 Signaling can Influence the Therapeutic Activities of BET Protein Inhibitors

Nirmalya Chatterjee  1 , Dirk Bohmann  2
Affiliations
Review

BET-ting on Nrf2: How Nrf2 Signaling can Influence the Therapeutic Activities of BET Protein Inhibitors

Nirmalya Chatterjee et al. Bioessays. 2018 May.

Abstract

BET proteins such as Brd3 and Brd4 are chromatin-associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti-inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug _targets. Small molecules that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of _targeting a Nrf2 or BET proteins individually.

Keywords: AML; BET proteins; COPD; Nrf2 signaling; cancer; inflammation; oxidative stress.

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Conflict of interest statement

Competing interests

The authors declare no competing interest

Figures

Figure 1.
Figure 1.. The BET-Nrf2 regulatory network as a _target for combination drug treatment.
(A) BET proteins are implicated in cancer and inflammation. BET proteins inhibit Nrf2, the master regulator of the cellular oxidative stress response. Nrf2 signaling has anti-inflammatory effects but can also promote survival of cancer cells. (B) Combination of Keap1 inhibitors and BET protein inhibitors for the treatment of inflammatory pathologies. Synergistic activation of Nrf2 activity suppresses oxidative stress and inflammation while the suppression of BET proteins prevents their proinflammatory effects. (C) Combination of BET protein inhibitors and Nrf2 inhibitors for the treatment of cancer. BET inhibitors cause a loss of tumor-promoting functions of BET proteins while Nrf2 inhibitors prevent the Nrf2-activating “side effect” of BET protein suppression that would otherwise protect cancer cells from oxidative stress due to high metabolic rates or cancer therapeutics.
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