Nature communications · 2025
Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.
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Zhou Heming, Chen Huarong, Liu Weixin, Liang Cong, Wang Shiyan, Yuan Kai, Cheung Alvin Ho Kwan, Wu Yuet, Kang Wei, Cheung Henley, Ding Yanqiang, Wei Qinyao, Su Hao, Li Tianhui, Luo Weimei, Chen Sujun, Wong Chi Chun, Yu Jun
Аннотация
The role of RNA N6-methyladenoine (m6A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m6A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquitination and degradation. By boosting CSCs, ALKBH5 overexpression elicit chemoresistance in CSCs, PDOs and transgenic mice. Targeting of ALKBH5 by knockout or VNPs-siALKBH5 synergizes with chemotherapy to trigger tumor regression in CSCs-/PDOs-derived xenografts and ALKBH5 knockout mice. Together, we reveal that ALKBH5 is essential for colorectal CSCs and is a therapeutic target for overcoming CRC chemoresistance.