Bai Xiaoming, Duan Tinghong, Shao Jiaofang, Zhang Yutong, Xing Guangyuan, Wang Jie, Liu Xue, Wang Min, He Yuanqiao, Wang Hai, Zhang Zhi-Yuan, Ni Min, Zhou Jin-Yong, Pan Jinshun
Department of Pathology, Nanjing Medical University, Nanjing, PR China.
Department of Pathology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China.
Oncogene. 2025 Mar 16. doi: 10.1038/s41388-025-03337-9.
Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future.
化疗耐药是结直肠癌（CRC）治疗中的一个重大挑战。然而，化疗耐药的潜在机制仍不清楚。CBX3促进CRC的增殖和转移。然而，CBX3在化疗耐药中的作用和机制仍不清楚。因此，我们旨在研究CBX3对CRC多药耐药的影响及机制。我们的研究表明，CBX3表达水平较高与较差的生存率相关，尤其是在化疗后病情进展的组中。CBX3过表达增加了伊立替康和奥沙利铂耐药性，而CBX3敲低抑制了CRC细胞中的多药耐药性。此外，CBX3抑制与多药耐药相关的铁死亡，铁死亡激活剂阻止了CBX3过表达介导的细胞存活。RNA测序显示NRF2信号通路参与了这一过程。CBX3通过直接结合Cullin3（CUL3）的启动子来上调NRF2蛋白表达，从而抑制CUL3转录和CUL3介导的NRF2降解。此外，谷胱甘肽过氧化物酶2（GPX2）是CRC化疗耐药中CBX3-NRF2通路的下游。NRF2抑制剂ML385抑制了GPX2表达，并增加了PDX模型中的铁死亡。我们的研究确定CBX3/NRF2/GPX2轴可能是介导CRC多药耐药的一条新信号通路。本研究提出未来开发新的癌症治疗策略以克服耐药性。
