Xu Changwei, Shen Tong, Feng Lin, Wang Lei, Li Shisen, Ding Ruxin, Geng Zhi, Fan Minmin, Xiao Tian, Zheng Jianyong, Shen Liangliang, Qu Xuan
Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China.
Department of Digestive Surgery, Xi'an International Medical Center, Xi'an, Shaanxi, China.
Redox Biol. 2025 Jun;83:103647. doi: 10.1016/j.redox.2025.103647. Epub 2025 Apr 30.
Drug resistance in colorectal cancer (CRC) poses a major challenge for cancer therapy and stands as the primary cause of cancer-related mortality. The N6-methyladenosine (m6A) modification has emerged as a pivotal regulator in cancer biology, yet the precise m6A regulators that propel CRC progression and chemoresistance remain elusive. Our study established a significant correlation between m6A regulatory gene expression profiles and CRC severity. Notably, based on the knockout cellular and mouse model created by CRISPR/Cas9-mediated genome engineering, we identified m6A demethylase FTO emerged as a pivotal orchestrator of CRC chemoresistance through the regulation of NUPR1, a critical transcription factor involved in iron homeostasis via LCN2 and FTH1. Mechanistic study revealed that FTO stabilized NUPR1 mRNA by specifically targeting the +451 m6A site, thereby preventing YTHDF2-mediated degradation of NUPR1 mRNA. Moreover, the simultaneous targeting of FTO and NUPR1 dramatically enhanced the efficacy of chemotherapy in CRC cells. Our findings underscore the potential of modulating the m6A methylome to overcome chemoresistance and highlight the FTO-NUPR1 axis as a critical determinant in CRC pathobiology.
结直肠癌（CRC）中的耐药性是癌症治疗面临的一项重大挑战，也是癌症相关死亡的主要原因。N6-甲基腺苷（m6A）修饰已成为癌症生物学中的关键调节因子，但推动CRC进展和化疗耐药的确切m6A调节因子仍不清楚。我们的研究建立了m6A调节基因表达谱与CRC严重程度之间的显著相关性。值得注意的是，基于CRISPR/Cas9介导的基因组工程创建的基因敲除细胞和小鼠模型，我们发现m6A去甲基化酶FTO通过调节NUPR1（一种通过LCN2和FTH1参与铁稳态的关键转录因子），成为CRC化疗耐药的关键协调因子。机制研究表明，FTO通过特异性靶向+451 m6A位点稳定NUPR1 mRNA，从而防止YTHDF2介导的NUPR1 mRNA降解。此外，同时靶向FTO和NUPR1可显著增强CRC细胞化疗的疗效。我们的研究结果强调了调节m6A甲基化组以克服化疗耐药性的潜力，并突出了FTO-NUPR1轴是CRC病理生物学的关键决定因素。
