A couple more additions to this story, thanks to Klendathu Capitalist (@KlendathuCap) on Twitter:

The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.

"The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress."

Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression

"Highlights:

•Brd4 was up-regulated in the progression of renal fibrosis.

•Brd4 inhibitor JQ1 prevented renal fibrosis and delayed the fibrotic progression.

•Brd4 inhibition blocked TGF-β1-induced oxidative stress and fibrosis through Nox4.

•Brd4 regulated Nox4 expression via Smad and ERK pathways.

Abstract

Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-β1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-β1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-β1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-β-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target."