The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer

Abstract

Background Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Efficacy of the bromodomain 4 (BRD4) inhibitor JQ1 has been reported for the treatment of various human cancers, but its potential impact on EC remains unclear. We therefore aimed to elucidate the function of BRD4 and the effects of JQ1 in EC in vivo and in vitro. Methods The mRNA expression of BRD4 was evaluated using datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). BRD4 protein expression in EC tissues was measured using immunohistochemistry (IHC) assays. The effects of JQ1 on EC were determined by using MTT and colony formation assays, flow cytometry and xenograft mouse models. The underlying mechanism was also examined by western blot and small interfering RNA (siRNA) transfection. Results BRD4 was overexpressed in EC tissues, and the level of BRD4 expression was strongly related to poor prognosis. The BRD4-specific inhibitor JQ1 suppressed cell proliferation and colony formation and triggered cell apoptosis, cell cycle arrest, and changes in the expression of proteins in related signaling pathways. Moreover, JQ1 decreased the protein expression of BRD4 and c-Myc, and knockdown of BRD4 or c-Myc reduced the viability of EC cells. Intraperitoneal administration of JQ1 (50 mg/kg) significantly suppressed the tumorigenicity of EC cells in a xenograft mouse model. Conclusion Our results demonstrate that BRD4 is a potential marker of EC and that the BRD4 inhibitor JQ1 is a promising chemotherapeutic agent for the treatment of EC.

Transcriptional factor BRD4 promotes the stemness of esophageal cancer by activating the nuclear PD‐L1/RelB axis

“…BRD4, a member of the bromodomain and extraterminal domain (BET) family, has been implicated in various cancers, including endometrial cancer 24 . In our study, we observed upregulated expression of BRD4 in ECSCs compared to nonstem cancer cells.…”

“…BRD4, a member of the bromodomain and extraterminal domain (BET) family, has been implicated in various cancers, including endometrial cancer. 24 In our study, we observed upregulated expression of BRD4 in ECSCs compared to nonstem cancer cells. This upregulation was accompanied by enhanced sphere formation and increased expression of stem cell markers CD44 and CD133.…”

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment

“…Minnelide binds to the XBP subunit of the transcription factor II H (TFIIH)-BRD4 super-enhancer complex that regulates many targets, including c-Myc expression 9 . It was also reported that the anti-tumor activity of BRD4 inhibitor in TNBC was shown to be mediated by the downregulation of Myc expression 50 . Thus, the scienti c exploratory end points included the evaluation of Myc expression and accessibility of loci for the Myc gene in pre-and post-treatment tumors 24 .…”

Epigenetic regulation in cancer

“…Initial small‐molecule BET inhibitors, exemplified by JQ1, were instrumental in elucidating the oncogenic role of BET proteins and the consequent effects of BET inhibition on the expression of various oncogenes. This modulation of key oncogenes is believed to underlie the antitumorigenic properties of BET inhibitors observed in preclinical models 268,269 . Nonetheless, the clinical application of these agents has been constrained by their suboptimal pharmacokinetic profiles, including a brief half‐life and limited oral bioavailability.…”