YTHDF1 targets the chemotherapy response by suppressing NOTCH1-induced stemness in colorectal cancer

作者：Henley Cheung, Huarong Chen, D.M. Chen, Heming Zhou, Cong Liang, Weixin Liu, Alvin H.K. Cheung, Yanqiang Ding, Kai Yuan, X. Li, Yongxin Zhang, Shiyan Wang, Wei Kang, Ka-Fai TO, Housheng Hansen He, Chi Chun Wong, Jun Yu · 发表于：Signal Transduction and Targeted Therapy · 年份：2025 · DOI：10.1038/s41392-025-02507-1 · 被引用次数：6 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、interferon and immune responses

Abstract N 6 -methyladenosine (m 6 A) modification of mRNAs is a predominant epigenetic regulatory mechanism in tumor initiation and progression. Cancer stem cells (CSCs) are the key drivers of colorectal cancer (CRC) initiation and chemotherapy resistance. Here, we found that the m 6 A reader YT521-B homologous domain family, member 1 (YTHDF1), promotes CRC stemness, tumorigenesis, and chemotherapy resistance. YTHDF1 protein expression was positively correlated with CD133 and LGR5 expression in human CRC tissues (N = 184, P < 0.001 for both markers). YTHDF1 promoted m 6 A-dependent self-renewal in CSCs and patient-derived organoids and increased the tumor-initiating potential in vivo. Lgr5-specific Ythdf1 -KI mice presented accelerated Apc Min/+ ( P < 0.05) and AOM/DSS ( P < 0.05)-induced colorectal tumorigenesis, whereas Lgr5-specific Ythdf1 knockout in Apc Min/+ mice inhibited tumorigenesis ( P < 0.01). Integrative multiomic profiling revealed NOTCH1 as a downstream target. YTHDF1 binds m 6 A-modified NOTCH1 , promoting its translation and enhancing NOTCH signaling. NOTCH1 knockdown or blockade by the γ-secretase inhibitor DAPT abolished YTHDF1-mediated tumorigenesis in Ythdf1 knock-in mice ( P < 0.01). YTHDF1 promoted resistance to oxaliplatin and 5-fluorouracil in CSCs by inhibiting apoptosis and DNA damage. AOM/DSS-treated Ythdf1 knock-in mice presented increased resistance to oxaliplatin ( P < 0.001) and 5-fluorouracil ( P < 0.05). Translationally,...