BET bromodomain-containing protein 4 (BRD4), an epigenome reader works as an oncogene for several cancer types including those that develop in the skin. BRD4 inhibitors have been shown to have antitumor efficacy in multiple cancer models. Additional studies demonstrate the involvement of BRD4 in onsetting inflammation which is a key component of the pathogenesis of cancers including in the development of tumor growth conducive microenvironment. Here we show that a recently developed non-hyperlipidemic retinoid X receptors (RXR) agonist 9cUAB30 besides its anticancer properties also reduces UVB-induced inflammation in a murine model. The molecular mechanism underlying anti-inflammatory effect of 9cUAB30 is complex that involves epigenetic modulation of histones. Orally administered 9cUAB30 reduces BRD4 expression and its downstream signaling. 9cUAB30 mediated inhibition of BRD4 is also evidenced by the downregulation of acetylated histones such as H3K27ac, H3K18ac, H3K9ac, H4K8ac and H4K5ac. This is further confirmed by RNAseq data that show UVB-mediated alterations in multiple BRD4 target genes are attenuated by 9cUAB30 treatment. Furthermore, the BRD4 regulated cytokines such as IL6, IL12a, IL19, IL23, IL27, and IL33 which are induced by UVB, are attenuated by 9cUAB30 treatment. However, UVB induced additional multiple cytokines/chemokines. 9cUAB30 treatment was also successful in diminishing their levels significantly. These data support the notion that 9cUAB30 acts by targeting additional inflammation regulating pathways besides those regulated by BRD4 dependent epigenetic modulation. These initial effects in the tumor adjacent skin could be seen even in the SCCs and BCCs which progress from these early benign lesions suggesting that BRD4 mediated signaling is important during the entire pathogenesis of highly malignant cutaneous lesions. This is further confirmed by in vitroinvestigation employing Squamous cell carcinoma A431 and SCC13 cells in culture. Further evidence that 9cUAB30 acts via dampening BRD4 regulated pathways comes from genetic studies employing the knockdown and forced expression approaches. Our data also demonstrate that 9cUAB30 dependent majority of anti-inflammation and EMT blocking effects are mediated by targeting BRD4- NFkB /BRD4-Twist axis. In summary 9cUAB30 elaborates anti-inflammatory effects by targeting BRD4 regulated chromatin remodeling.
Citation Format: Mohammad Waseem, Mahendra P. Kashyap, Changzhao Li, Sandeep C. Chaudhary, Darshan S. Chandrashekar, Venkatram R. Atigadda, Sooryanarayana Varambally, Craig A. Elmets, Mohammad Athar. 9cis-retinoic UAB30 inhibits UVB-induced pro-inflammatory cytokines/chemokines signaling via targeting Bromodomain-4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-247.