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

ABSTRACT: 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 ubiqu

SUBMITTER: Zhou H 

PROVIDER: S-EPMC12824147 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature