ALKBH5 promotes the progression of cisplatin-resistant oral squamous cell carcinoma by regulating FOXA1 expression via m6A RNA methylation : Funding

  • Daru. 2026 Jun 6;34(2):31. doi: 10.1007/s40199-026-00614-0.
Ying Wang  1 ,  Hui-Xin Yang  1 ,  Yu-Jia Gu  1 ,  Mei Tian  1 ,  Qi-Feng Geng  2
Affiliations
  • 1. The Fifth Outpatient Department, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
  • 2. The Fifth Outpatient Department, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China. [email protected].
PMID: 42251238 DOI: 10.1007/s40199-026-00614-0
Abstract

Background: Oral squamous cell carcinoma (OSCC) accounts for the vast majority of oral Cancer cases. Accumulating evidence has implicated both AlkB homolog 5 (ALKBH5) and forkhead box protein A1 (FOXA1) in the emergence of cisplatin resistance in OSCC. This study aimed to define their functional roles and elucidate the underlying molecular mechanisms.

Methods: The expression of ALKBH5, FOXA1, and YTHDF2 was assessed by qPCR and Western blot. Cisplatin-resistant cell lines (H357 CisR and SCC4 CisR) were established via stepwise dose escalation. To investigate key functional phenotypes, a series of assays were employed: CCK-8 for viability, colony formation for proliferation, and Transwell for migration and invasion. Bioinformatics (SRAMP, RM2Target) predicted m⁶A sites on FOXA1 and its binding with ALKBH5, which were validated by MeRIP-qPCR and RIP. FOXA1 mRNA stability was measured by actinomycin D assay.

Results: ALKBH5 and FOXA1 were upregulated in cisplatin-resistant OSCC, with FOXA1 essential for maintaining oncogenic phenotypes. Bioinformatic and biochemical analyses confirmed FOXA1 as a direct target of ALKBH5. ALKBH5 demethylates FOXA1 mRNA, stabilizing its transcript and enhancing its expression by inhibiting YTHDF2-mediated degradation. Functionally, ALKBH5 overexpression reversed the tumor-suppressive effects of FOXA1 knockdown.

Conclusion: Our study demonstrates that ALKBH5 promotes cisplatin resistance in OSCC through m6A-dependent demethylation of FOXA1 transcripts, highlighting the ALKBH5-FOXA1 axis as a promising therapeutic target for overcoming this resistance.

Keywords
ALKBH5; Cisplatin-resistant oral squamous cell carcinoma; FOXA1; YTHDF2; m6A RNA methylation.
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