BRD4 drives esophageal squamous cell carcinoma growth by recruiting TP73 to promote RCC2 expression

Low patient survival rates of esophageal squamous cell carcinoma are attributed mainly to a lack of insight regarding the molecular mechanisms governing its progression. Despite the prevalence of genetic mutations, targeted therapies have yet to be developed due to technical limitations in ESCC. Alterations in epigenetic modulators are essential to cancer development and prognosis. BRD4, a chromatin reader protein, plays an essential role in regulating oncogene expression. Here, we investigated the contributing role of BRD4 and its related mechanisms in the context of ESCC tumor progression. Our observations showed that BRD4 transcript and protein levels are increased in ESCC patient tissues. Genetic or pharmacological inhibition of BRD4 suppressed ESCC cell proliferation in vitro and in vivo. Proteomic and transcriptomic analyses were subsequently used to deduce potential targets of BRD4. Mechanistic studies showed that RCC2 is a downstream of BRD4. Inhibition of either BRD4 or RCC2 resulted in decreased cell proliferation. BRD4 was found to interact with TP73 directly, facilitate the recruitment of TP73 to the promoter region of RCC2, and subsequently modulate RCC2 transcription. Furthermore, targeting BRD4 with inhibitors significantly decreased tumor volume in ESCC PDX models, providing evidence for the role of BRD4 in tumor progression. Collectively, BRD4 recruits TP73 to the promoter of RCC2, thereby regulating RCC2 expression. BRD4 promotes ESCC tumor growth by up-regulating RCC2 expression. Overall, BRD4 inhibition could be a promising therapeutic strategy in ESCC by downregulating RCC2.