Inhibition of BRD4 Suppresses Cell Proliferation and Induces Apoptosis in Renal Cell Carcinoma

Abstract

Background/Aims: Renal cell carcinoma (RCC) remains an intractable genitourinary malignancy. Resistance to chemotherapy or targeted therapies in RCC is presumably due to the complicated underlying molecular mechanisms and insufficient understanding. The aim of this research was to assess the expression and role of bromodomain-4 protein (BRD4) in RCC and evaluate the effects of BRD4 inhibitor JQ1 for RCC treatment. Methods: BRD4 expressionlevels were assessed by qRT-PCR and western blot in RCC tissues and cells. The effects of BRD4 knockdown or JQ1 on RCC cells were assessed by MTT assay and flow cytometry. The effects of in vivo treatment were evaluated through xenograft experiments. Results: BRD4 is significantly overexpressed in RCC, and is related to tumor stage and lymph node metastasis. Inhibition of BRD4 suppressed RCC cell proliferation, induced cell apoptosis in vitro and repressed tumor growth in vivo. Inhibition of BRD4 decreased BCL2 and C-MYC expression while increased BAX and cleaved caspase3 expression, and strikingly diminished the recruitment of BRD4 to BCL2 promoter. Conclusions: Our research reveals that BRD4 probably play a critical role in RCC progression, and is a new promising target for pharmacological treatment directed against this intractable disease.

Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

“…These findings support the hypothesis that different mechanisms may be responsible for the efficacy of JQ1 in NETs, and these may involve the apoptotic pathway, as indicated by our RNA-Seq analysis that revealed four apoptosis-associated genes (Capn9, Dffb, Birc3 and Nfkb1) to be downregulated by JQ1 treatment. Birc3 encodes cIAP2, which is an E3 ubiquitin protein ligase that is a member of the inhibitors of apoptosis proteins (IAP) family, and increases cIAP2 expression that can lead to evasion of caspase-mediated apoptosis in different cancers including gastric and gallbladder cancers and glioblastoma (Wang et al 2016, Jiang et al 2017, Gowda Saralamma et al 2018. In addition, cIAP2 has been reported to activate NFκB (encoded by Nfkb1) signalling, which also has roles in apoptosis regulation (Tchoghandjian et al 2013, Jiang et al 2017.…”

“…Epigenetic-targeting compounds are a new class of anti-tumour drugs, and one such family of small molecule bromo and extra-terminal domain (BET) inhibitors, which target the bromodomains (BRDs) of the protein family members BRD2, BRD3, BRD4 and BRDT that bind acetylated residues on histones that regulate gene expression, and particularly those of tissue-specific genes (Filippakopoulos et al 2010), have been shown in preclinical in vitro and in vivo studies to have efficacy in a number of tumour types including pancreatic neuroendocrine tumours, glioma, nuclear protein in testis (NUT)-midline carcinoma, leukaemias and renal cell carcinoma (Beesley et al 2014, Coude et al 2015, Ishida et al 2017a,b, Leal et al 2017, Lines et al 2017, Wu et al 2017. Moreover, in order to determine if BET inhibitors may also represent an effective novel therapy for corticotrophinomas in reducing proliferation and increasing apoptosis of these pituitary cells, we first investigated the mouse corticotroph tumour cell line AtT20 for expression of the BET protein family members and then the effects of the BET inhibitors JQ1 and PFI-1 on proliferation, apoptosis and ACTH secretion by these pituitary cells.…”

Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells

“…Notably, in the case of BET‐inhibitors, genomic evidence was observed from the PDCs established from both RCC.1 and RCC.3 suggesting that epigenetic mechanisms should be further explored in RCC for clinical relevance. The pro‐oncogenic role of BRD4 was recently evaluated in RCC through in vitro and in vivo experiments, which also suggested a treatment rationale for RCC patients …”

K6PC-5 Activates SphK1-Nrf2 Signaling to Protect Neuronal Cells from Oxygen Glucose Deprivation/Re-Oxygenation

“…Forty micrograms of lysate proteins per lane were separated on 10-12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (PAGE) gels, then transferred to polyvinylidene difluoride (PVDF) membrane (Millipore, Suzhou, China) [22]. After blocking, the blots were incubated with the appropriate primary and secondary antibodies.…”