Enhancer remodeling activates Notch signaling to confer chemoresistance in advanced nasopharyngeal carcinoma [ChIP-Seq]

Acquired resistance to chemotherapy is one of the major causes of mortality in advanced nasopharyngeal carcinoma (NPC). However, effective strategies are limited and the underlying molecular mechanisms remain elusive. Using an established NPC cellular model, we demonstrated that the acquisition of chemoresistance was accompanied by massive enhancer remodeling, resulting in aberrant hyperactivation of Notch signaling pathway in NPC. Transcriptomic profiling analysis showed that hyperactivity of Notch signaling pathway was associated with chemoresistance in advanced NPC patients. In addition, overexpression of Notch3-slug axis was correlated with relapses and metastasis of NPC. Importantly, we showed that genetic or pharmacological perturbation of Notch3 could overcome the chemoresistance of NPC in both in vitro and in vivo models. Together, our study indicated that genome-wide enhancer reprogramming activates Notch signaling pathway to confer chemoresistance of NPC, suggesting that targeting Notch3 could provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC. 1. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq ) for H3K27Ac, H3K4me3 in 5-8F P and 5-8F R cells