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Published on: July 22, 2020
YTHDF1 targets the chemotherapy response by suppressing NOTCH1-induced stemness in colorectal cancer
Henley Cheung1, Huarong Chen1,2, Danyu Chen1
1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
Abstract:
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.
Insights
The m6A reader YTHDF1 drives colorectal cancer (CRC) stemness and chemoresistance by activating NOTCH1 signaling. Targeting YTHDF1 offers a promising strategy to enhance chemotherapy efficacy in CRC patients.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) modification is a key epigenetic regulator in cancer.
- Cancer stem cells (CSCs) drive colorectal cancer (CRC) initiation and treatment resistance.
- YTHDF1 is an m6A reader protein implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of YTHDF1 in colorectal cancer stemness, tumorigenesis, and chemotherapy resistance.
- To elucidate the downstream molecular mechanisms by which YTHDF1 exerts its effects in CRC.
- To evaluate the therapeutic potential of targeting YTHDF1 in CRC treatment.
Main Methods:
- Analysis of YTHDF1 expression in human CRC tissues and correlation with CSC markers (CD133, LGR5).
- In vitro studies using CSCs and patient-derived organoids to assess YTHDF1's role in self-renewal and chemoresistance.
- In vivo studies using genetically engineered mouse models (Ythdf1-KI and knockout) and xenograft models to evaluate tumorigenesis and treatment response.
- Integrative multiomic profiling to identify downstream targets, followed by functional validation (e.g., NOTCH1 knockdown, DAPT treatment).
- In vivo therapeutic evaluation of YTHDF1 targeting using VNP-encapsulated siYTHDF1 and salvianolic acid C, alone and in combination with chemotherapy.
Main Results:
- YTHDF1 expression positively correlates with CSC markers in human CRC.
- YTHDF1 promotes CSC self-renewal, tumor initiation, and colorectal tumorigenesis in mouse models.
- YTHDF1 enhances NOTCH1 translation and signaling, driving CRC stemness and tumorigenesis.
- YTHDF1 confers resistance to oxaliplatin and 5-fluorouracil by inhibiting apoptosis and DNA damage.
- Targeting YTHDF1 in vivo significantly inhibits tumor growth and enhances the efficacy of standard chemotherapies.
Conclusions:
- YTHDF1 is a critical driver of colorectal cancer stemness and chemoresistance.
- The YTHDF1/NOTCH1 axis plays a crucial role in CRC progression and therapeutic resistance.
- Targeting YTHDF1 represents a promising therapeutic strategy to improve treatment outcomes in colorectal cancer.
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