Bromodomain protein BRD4 inhibitor JQ1 regulates potential prognostic molecules in advanced renal cell carcinoma

Abstract

Sunitinib is a standard molecular-targeted drug used as a first-line treatment for metastatic clear cell renal cell carcinoma (ccRCC); however, resistance to sunitinib has become a major problem in medical practice. Recently, bromodomain containing 4 (BRD4), a member of the bromodomain family proteins, was identified as a promising therapeutic target, and its inhibitor JQ1 has been shown to have inhibitory effects in various human cancers. However, the anti-cancer effects of JQ1 in ccRCC, particularly sunitinib-resistant ccRCC, are still unclear. Here, we aimed to elucidate the anti-cancer effects of JQ1 and the mechanisms underlying BRD4 inhibition in sunitinib-sensitive and -resistant ccRCCs. Analysis of The Cancer Genome Atlas (TCGA) ccRCC cohort showed that patients with high BRD4 expression had shorter overall survival than those with low expression. JQ1 treatment significantly inhibited tumor growth of sunitinib-sensitive and -resistant ccRCC cells in part through MYC regulation. Based on RNA sequencing analyses of ccRCC cells treated with JQ1 to elucidate the mechanisms other than MYC regulation, we identified several oncogenes that may be potential therapeutic targets or prognostic markers; patients with high expression of SCG5, SPOCD1, RGS19, and ARHGAP22 had poorer overall survival than those with low expression in TCGA ccRCC cohort. Chromatin immunoprecipitation assays revealed that these oncogenes may be promising BRD4 targets, particularly in sunitinib-resistant ccRCC cells. These results identified SCG5, SPOCD1, RGS19, and ARHGAP22 as potential prognostic markers and showed that BRD4 inhibition may have applications as a potential therapeutic approach in sunitinib-sensitive and -resistant ccRCC.

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

“…Based on its strong effect on transcriptional regulation, the role of the BET family in the promotion of the biological behaviour of cancer cells has been identified . Furthermore, the BRD4 inhibitor (+)‐JQ1 (JQ1) has been shown to suppress the proliferation of cancer cells, indicating that JQ1 may be a new therapeutic agent for cancer treatment . However, the clinical application of JQ1 is limited .…”

“…Furthermore, the BRD4 inhibitor (+)‐JQ1 (JQ1) has been shown to suppress the proliferation of cancer cells, indicating that JQ1 may be a new therapeutic agent for cancer treatment . However, the clinical application of JQ1 is limited . Since some cancer cells are insensitive to JQ1 treatment, subsequently leading to treatment failure .…”

“…25 However, the clinical application of JQ1 is limited. 25 Since some cancer cells are insensitive to JQ1 treatment, subsequently leading to treatment failure. 26,40 Therefore, new drugs or models need to be identified to overcome the obstacles associated with JQ1 treatment.…”

“…The important roles of BRD4 in transcriptional activation and the initiation of tumour formation have led to the consideration of selective inhibition of BRD4 as a promising therapeutic strategy against cancer . The amino‐terminal bromodomains of BRD4 have been targeted using several selective small‐molecule inhibitors, such as I‐BET762 and JQ1, and promising antiproliferative effects have been observed along with promising clinical significance in a range of cancers . The first‐in class thienodiazepine small‐molecule JQ1 binds to BET protein bromodomains with acute complementarity and an affinity in nanomoles, resulting in transient, competitive and robust displacement of BRD4 from acetylated chromatin, thus selectively occluding transactivation of specific gene sets in a context, or dose‐dependent manner .…”

Development and evaluation of a novel series of Nitroxoline-derived BET inhibitors with antitumor activity in renal cell carcinoma

“…Knocking down BRD2 or BRD4 only moderately inhibited RCC cell proliferation, which might be due to the compensatory effect by other BET family members, while knocking down both BRD2 and BRD4 resulted in remarkable suppression of RCC cell proliferation and reduced expression of c-Myc onco-protein. Two previous studies 26 , 27 used genetic knockdown to assess the role of BRD4 in RCC, however, the role of other members (BRD2, BRD3) in BET family in RCC remains unclear to date. Thus our study consisted of and further characterized the role of BET family members in RCC, suggesting that BET family proteins might represent potential therapeutic targets in the treatment of RCC.…”