MYCN-mediated regulation of the HES1 promoter enhances the chemoresistance of small-cell lung cancer by modulating apoptosis

摘要

MYCN, a member of the MYC family, is correlated with tumorigenesis, metastasis and therapy in many malignancies; however, its role in small-cell lung cancer (SCLC) remains unclear. In this study, we sought to identify the function of MYCN in SCLC chemoresistance and found that MYCN is overexpressed in chemoresistant SCLC cells. We used MYCN gain- and loss-of- function experiments to demonstrate that MYCN promotes in vitro and in vivo chemoresistance in SCLC by inhibiting apoptosis. Mechanistic investigations showed that MYCN binds to the HES1 promoter and exhibits transcriptional activity. Furthermore, MYCN mediated SCLC chemoresistance through HES1. Accordingly, the NOTCH inhibitor FLI-60 derepressed HES1 and diminished MYCN-induced chemoresistance in SCLC. Finally, the positive correlation between HES1 and MYCN was confirmed in SCLC patients. Chemoresistant SCLC patients had higher expression levels of MYCN and HES1 than patients without chemoresistant SCLC. MYCN overexpression was related to advanced clinical stage and shorter survival in SCLC. In conclusion, our study revealed that MYCN and HES1 may be potential therapeutic targets and promising predictors for SCLC.