Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
Cell Death Dis. 2023 Aug 10;14(8):513. doi: 10.1038/s41419-023-06028-z.
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.
获得性化疗耐药是晚期鼻咽癌（NPC）患者死亡的主要原因之一。然而，有效的治疗策略有限，其潜在的分子机制仍难以捉摸。在这项研究中，通过对 23 个肿瘤组织的转录组谱分析，我们发现 NOTCH3 在化疗耐药 NPC 患者中异常高表达，NOTCH3 过表达与不良临床结局呈正相关。在机制上，我们使用已建立的 NPC 细胞模型证明，增强子重塑导致化疗耐药 NPC 中 NOTCH3 的异常过度激活。我们进一步表明，NOTCH3 上调 SLUG 诱导 NPC 细胞的化疗耐药性，并且 SLUG 的高表达预示着更差的预后。NOTCH3 的遗传或药物干扰赋予 NPC 细胞体外的化疗敏感性，而过表达 NOTCH3 则增强 NPC 细胞在体内的化疗耐药性。综上所述，这些数据表明全基因组增强子重编程激活 NOTCH3 赋予 NPC 化疗耐药性，提示靶向 NOTCH3 可能为有效治疗晚期化疗耐药 NPC 提供一种潜在的治疗策略。
