METTL1-driven epitranscriptomic enhancement of TXNDC12 boosts c-Myc stability through USP5 in HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy worldwide. Advancing understanding of the molecular mechanisms driving tumor progression and resistance to therapy is essential for developing new strategies to improve patient outcomes in HNSCC. Here we demonstrate that elevated expression of thioredoxin domain-containing protein 12 (TXNDC12) in HNSCC is associated with adverse clinical outcomes and reduced survival. Modulating TXNDC12 levels demonstrates that its reduction curtails aggressive tumor phenotypes and cisplatin resistance, while its overexpression exacerbates these characteristics. Comprehensive RNA transcriptomic analysis reveals that depletion of TXNDC12 leads to significant suppression of c-Myc signaling pathways. Mechanistically, TXNDC12 stabilizes c-Myc protein by promoting its interaction with USP5, thus preventing proteasomal degradation of c-Myc. Moreover, METTL1 enhances TXNDC12 mRNA stability via an m 7 G-dependent mechanism. Clinical validation underscores the importance of the METTL1-TXNDC12-c-Myc axis in HNSCC. Our findings reveal that METTL1-coupled epitranscriptomic upregulation of TXNDC12 in HNSCC enhances c-Myc signaling by promoting its USP5-mediated stability.