ALKBH5-IGF2BP2 Axis Mediates Prostate Cancer Progression and Docetaxel Resistance via m6A-Stabilized CLSPN RNA

Prostate cancer (PCa) often progresses to castration-resistant PCa (CRPC), where docetaxel (DTX) resistance is a major challenge. We investigated the role of the m6A demethylase ALKBH5 in this resistance. ALKBH5 expression was significantly reduced in CRPC clinical samples. Functionally, overexpressing ALKBH5 inhibited PCa cell proliferation and migration, while its knockdown enhanced these effects and increased DTX resistance. Conversely, restoring ALKBH5 or knocking down the m6A reader IGF2BP2 reversed resistance. Multi-omics analysis identified CLSPN, a DNA replication stress regulator, as a key downstream target. Mechanistically, ALKBH5-mediated m6A demethylation reduces CLSPN mRNA stability in an IGF2BP2-dependent manner. Low ALKBH5, therefore, stabilizes CLSPN via IGF2BP2, promoting resistance. These findings, validated in clinical samples and organoid models, demonstrate that the ALKBH5-IGF2BP2 axis modulates DTX resistance in mCRPC through m6A-dependent regulation of CLSPN. Targeting this pathway represents a promising therapeutic strategy to overcome DTX resistance. Overall design: The C4-2 cells in the empty vector control group (NC) and the ALKBH5 overexpression group were subjected to m6A sequencing to analyze the differential patterns of m6A methylation modification. RNA sequencing was performed to analyze the differential mRNA expression in C4-2 cells following overexpression of the empty vector control (NC) and ALKBH5 (i.e. *-input samples)