ALKBH5-IGF2BP2 axis mediates prostate cancer progression and docetaxel resistance via m6A-stabilized CLSPN RNA

  • iScience. 2025 Sep 9;28(10):113520. doi: 10.1016/j.isci.2025.113520.
Yutong Chen  1  2 ,  Yang Li  1  2 ,  Zongzhu Liang  1  2 ,  Zhao Yang  1  2 ,  Haotian Ren  1  2 ,  Wanqing Wei  3 ,  Yuanjie Niu  1  2 ,  Zhiqun Shang  1  2
Affiliations
  • 1. Department of Urology, Tianjin Key Laboratory of Urology Basic Medicine, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China.
  • 2. Tianjin Institute of Urology, Tianjin, China.
  • 3. Department of Urology, Lianshui People's Hospital of Kangda College Affiliated to Nanjing Medical University, Jiangsu, China.
PMID: 41069850 DOI: 10.1016/j.isci.2025.113520
Abstract

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 metastatic CRPC through m6A-dependent regulation of CLSPN. Targeting this pathway represents a promising therapeutic strategy to overcome DTX resistance.

Keywords
Cancer; Molecular interaction; Molecular mechanism of gene regulation.
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