BET inhibitor blocks the oncogenic function of nucleophosmin 1 in castration-resistant prostate cancer by interfering with the c-Myc signaling pathway

Abstract Background: Nucleophosmin 1 (NPM1) is a multifunctional protein that promotes tumor progression in some solid tumors and has also been reported to be capable of predicting poor prognosis of prostate cancer (PCa). However, whether and how NPM1 exerts such malignant potentials in castration-resistant prostate cancer (CRPC) remain elusive. Methods: The effects of NPM1 on PCa and CRPC and the intervention of BET inhibitors were investigated by detecting the proliferation and invasion of PCa and CRPC cells in vitro using MTS, transwell and colony formation assays, and the tumor growth in castrated NOD/SCID mice. Expression levels of related genes involved in signaling pathways were examined by western blot and qRT-PCR assays in vitro, and immunohistochemical staining analysis in patient PCa specimens. The interaction between NPM1 and bromodomain-containing protein 4 (BRD4) was determined by coimmunoprecipitation assays.Results: we showed that NPM1 was overexpressed in PCa and CRPC cells and tissues and that the dysregulation of NPM1 promoted PCa and CRPC cell proliferation and invasion. We also demonstrated that NPM1 transcriptionally upregulated c-Myc expression in CRPC cells. Furthermore, we detected a positive correlation between NPM1 and c-Myc expressions in patient PCa specimens. Importantly, the NPM1-upregulated c-My expression was diminished by blockade of BRD4 in CRPC cells, and treatment with bromodomain and extra-terminal domain (BET) inhibitor JQ1 combined with NPM1 inhibition suppressed the malignant progression of CRPC in vitro and in vivo.Conclusion: These results indicate a novel mechanism by which NPM1 promotes CRPC progression through the c-Myc-mediated signaling pathway via BRD4 and that NPM1 may be a previously unrecognized PCa driver gene that could be a potential target for PCa and CRPC treatment, and that BET inhibitors combined with NPM1 inhibition may also be an alternative strategy for CRPC treatment.