Targeting of the m6A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer
The role of RNA N<sup>6</sup>-methyladenoine (m<sup>6</sup>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<sup>6</sup>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.
Authors
- Sujun Chen (ORCID: https://orcid.org/0000-0002-1941-3951)
- Alvin H.K. Cheung (ORCID: https://orcid.org/0000-0002-3913-8117)
- Hao Su (ORCID: https://orcid.org/0000-0002-7621-8730)
- Henley Cheung (ORCID: https://orcid.org/0000-0003-4607-4999)
- Chi Chun Wong (ORCID: https://orcid.org/0000-0003-1362-3541)
- Jun Yu (ORCID: https://orcid.org/0000-0003-3435-6550)
- Kai Yuan (ORCID: https://orcid.org/0000-0002-4777-4076)
- Qinyao Wei (ORCID: https://orcid.org/0009-0006-7809-3384)
- Huarong Chen (ORCID: https://orcid.org/0000-0003-2192-1864)
- Tianhui Li (ORCID: https://orcid.org/0000-0001-6396-0998)
- Yanqiang Ding (ORCID: https://orcid.org/0000-0002-7740-6696)
- Wei Kang (ORCID: https://orcid.org/0000-0002-4651-677X)
- Wenxin Luo (ORCID: https://orcid.org/0009-0008-9233-8848)
- Weixin Liu (ORCID: https://orcid.org/0000-0002-1650-0371)
- Shiyan Wang (ORCID: https://orcid.org/0000-0002-8240-7933)
- Cong Liang (ORCID: https://orcid.org/0000-0002-5572-5354)
- Yuet Wu
- Heming Zhou (ORCID: https://orcid.org/0000-0001-5460-3438)
Institutions
- Sun Yat-sen University (CN)
- Chinese University of Hong Kong (HK)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Prince of Wales Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-13
- DOI
- https://doi.org/10.1038/s41467-025-67502-0
- Citations
- 3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42