Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma

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. In this study, through transcriptomic profiling analysis of 23 tumor tissues, we found that NOTCH3 was aberrantly highly expressed in chemoresistance NPC patients, with NOTCH3 overexpression being positively associated with poor clinical outcome. Mechanistically, using an established NPC cellular model, we demonstrated that enhancer remodeling driven aberrant hyperactivation of NOTCH3 in chemoresistance NPC. We further showed that NOTCH3 upregulates SLUG to induce chemo-resistance of NPC cells and higher expression of SLUG have poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 conferred chemosensitivity of NPC in vitro and overexpression of NOTCH3 enhanced chemoresistance of NPC in vivo. Together, these data indicated that genome-wide enhancer reprogramming activates NOTCH3 to confer chemoresistance of NPC, suggesting that targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC.

Automated summary

Through transcriptomic profiling analysis of 23 tumor tissues, it was found that NOTCH3 was highly expressed in chemoresistance nasopharyngeal carcinoma (NPC) patients, and its overexpression was associated with poor clinical outcome. Mechanistically, enhancer remodeling was shown to drive the aberrant hyperactivation of NOTCH3 in chemoresistant NPC. Notably, NOTCH3 was found to upregulate SLUG to induce chemo-resistance of NPC cells, and higher expression of SLUG was associated with poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 enhanced chemosensitivity of NPC in vitro, while overexpression of NOTCH3 increased chemoresistance of NPC in vivo. Targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC.