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<p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>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<sup>6</sup>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, <i>P</i> &lt; 0.001 for both markers). YTHDF1 promoted m<sup>6</sup>A-dependent self-renewal in CSCs and patient-derived organoids and increased the tumor-initiating potential in vivo. Lgr5-specific <i>Ythdf1</i>-KI mice presented accelerated <i>Apc</i><sup><i>Min/+</i></sup> (<i>P</i> &lt; 0.05) and AOM/DSS (<i>P</i> &lt; 0.05)-induced colorectal tumorigenesis, whereas Lgr5-specific <i>Ythdf1</i> knockout in <i>Apc</i><sup><i>Min/+</i></sup> mice inhibited tumorigenesis (<i>P</i> &lt; 0.01). Integrative multiomic profiling revealed NOTCH1 as a downstream target. YTHDF1 binds m<sup>6</sup>A-modified <i>NOTCH1</i>, promoting its translation and enhancing NOTCH signaling. NOTCH1 knockdown or blockade by the γ-secretase inhibitor DAPT abolished YTHDF1-mediated tumorigenesis in <i>Ythdf1</i> knock-in mice (<i>P</i> &lt; 0.01). YTHDF1 promoted resistance to oxaliplatin and 5-fluorouracil in CSCs by inhibiting apoptosis and DNA damage. AOM/DSS-treated <i>Ythdf1</i> knock-in mice presented increased resistance to oxaliplatin (<i>P</i> &lt; 0.001) and 5-fluorouracil (<i>P</i> &lt; 0.05). Translationally, in vivo targeting of YTHDF1 via VNP-encapsulated si<i>YTHDF1</i> or salvianolic acid C inhibited tumor growth (<i>P</i> &lt; 0.05 for both treatments) and increased treatment efficacy when VNP was combined with oxaliplatin (<i>P</i> &lt; 0.05, SAC: <i>P</i> &lt; 0.01) or 5-fluorouracil (<i>P</i> &lt; 0.05 for both treatments). In conclusion, YTHDF1 promotes stemness and chemoresistance in CRC via NOTCH1 activation. Targeting YTHDF1 is a promising strategy to improve the outcome of chemotherapy in CRC.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Henley Cheung,
  • Huarong Chen,
  • Danyu Chen,
  • Heming Zhou,
  • Cong Liang,
  • Weixin Liu,
  • Alvin Ho-Kwan Cheung,
  • Yanqiang Ding,
  • Kai Yuan,
  • Xiaoxing Li,
  • Yongxin Zhang,
  • Shiyan Wang,
  • Wei Kang,
  • Ka-Fai To,
  • Housheng He,
  • Chi Chun Wong,
  • Jun Yu

摘要

N6-methyladenosine (m6A) 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 m6A 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 m6A-dependent self-renewal in CSCs and patient-derived organoids and increased the tumor-initiating potential in vivo. Lgr5-specific Ythdf1-KI mice presented accelerated ApcMin/+ (P < 0.05) and AOM/DSS (P < 0.05)-induced colorectal tumorigenesis, whereas Lgr5-specific Ythdf1 knockout in ApcMin/+ mice inhibited tumorigenesis (P < 0.01). Integrative multiomic profiling revealed NOTCH1 as a downstream target. YTHDF1 binds m6A-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, in vivo targeting of YTHDF1 via VNP-encapsulated siYTHDF1 or salvianolic acid C inhibited tumor growth (P < 0.05 for both treatments) and increased treatment efficacy when VNP was combined with oxaliplatin (P < 0.05, SAC: P < 0.01) or 5-fluorouracil (P < 0.05 for both treatments). In conclusion, YTHDF1 promotes stemness and chemoresistance in CRC via NOTCH1 activation. Targeting YTHDF1 is a promising strategy to improve the outcome of chemotherapy in CRC.