Abstract
BRD4 has long been implicated in many different pathological processes, in particular, the development of cancer and inflammation. Pyroptosis is a newly recognized type of inflammatory programmed cell death. However, the correlation between BRD4 and pyroptosis in renal cell carcinoma (RCC) remains elusive. The present study demonstrates that BRD4 expression levels are markedly upregulated, while pyroptosis-associated proteins are significantly reduced, in RCC tissues and cells. Inhibition of BRD4, via either genetic knockdown or use of bromodomain inhibitor JQ1, prevented cell proliferation and epithelial-mesenchymal transition (EMT) progression and induced caspase-1-dependent pyroptosis in RCC both in vitro and in vivo. In addition, BRD4 inhibition suppressed proliferation and EMT though pyroptosis in vitro and in vivo. Moreover, NLRP3, which mediates caspase-1-dependent pyroptosis, was increased upon BRD4 inhibition. Furthermore, the transcriptional activity of NLRP3 was enhanced by BRD4 inhibition, and this enhancement was blocked by activation of NF-κB phosphorylation, indicating that NF-κB is an upstream regulator of NLRP3. Collectively, these results show that BRD4 inhibition prevents cell proliferation and EMT, and exerts an antitumor effect in RCC by activating the NF-κB-NLRP3-caspase-1 pyroptosis signaling pathway. Thus, BRD4 is a potential target for RCC treatment, and JQ1 shows promise as a therapeutic agent for this disease.