Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer

作者：Heming Zhou, Huarong Chen, Weixin Liu, Cong Liang, Shiyan Wang, Kai Yuan, Alvin H.K. Cheung, Yuet Wu, Wei Kang, Henley Cheung, Yanqiang Ding, Qinyao Wei, Hao Su, Tianhui Li, Weimei Luo, Sujun Chen, Chi Chun Wong, Jun Yu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-67502-0 · 被引用次数：6 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Congenital Diaphragmatic Hernia Studies

Abstract The role of RNA N 6 -methyladenoine (m 6 A) 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 m 6 A-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.