ALKBH5 demethylation modification of SE-lncRNA ZMIZ1-AS1 promotes FGFR1-mediated proliferation and invasive metastasis in osteosarcoma

  • Cell Mol Life Sci. 2025 Nov 22. doi: 10.1007/s00018-025-05969-2.
Yuanzhuang Zhang  1 ,  Yeqiu Xu  1 ,  Yuxin Bao  1 ,  Hanjie Zhai  1 ,  Chenghao Li  1 ,  Hongchao Shi  1 ,  Fu Ren  2  3 ,  Yong Wang  4
Affiliations
  • 1. Second Department of Spinal Surgery, Central Hospital Affiliated to Shenyang Medical College, No. 5 South Seven West Road, Tiexi, Shenyang, Liaoning, 110024, P.R. China.
  • 2. Key Laboratory of Human Ethnic Specificity and Phenomics of Critical Illness in Liaoning Province, Shenyang Medical College, Shenyang, Liaoning, 110000, P.R. China. [email protected].
  • 3. Department of Anatomy, School of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, 110000, P. R. China. [email protected].
  • 4. Second Department of Spinal Surgery, Central Hospital Affiliated to Shenyang Medical College, No. 5 South Seven West Road, Tiexi, Shenyang, Liaoning, 110024, P.R. China. [email protected].
PMID: 41275058 DOI: 10.1007/s00018-025-05969-2
Abstract

Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized Fibroblast Growth Factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention.

Keywords
ALKBH5; FGFR1; FOSL1; Osteosarcoma; PTBP1; Super-enhancer; ZMIZ1-AS1.
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