Targeting of the m<sup>6</sup>A eraser ALKBH5 suppresses stemness and chemoresistance of colorectal cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41390849.
- Also identified by DOI 10.1038/s41467-025-67502-0 and PMC identifier 12824147.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- AlkB Homolog 5, RNA Demethylase
- Colorectal Neoplasms
- Neoplastic Stem Cells
- Drug Resistance, Neoplasm