YTHDF2 drives oral squamous cell carcinoma progression via m6A-dependent degradation of MTUS1/ATIP1 mRNA and mitochondrial dysregulation

N6-methyladenosine (m⁶A), the most abundant RNA modification, regulates mRNA stability through reader proteins such as YTHDF2. Here, we investigate YTHDF2's role in oral squamous cell carcinoma (OSCC) progression. Clinical analyses revealed elevated YTHDF2 expression in OSCC tumors compared to normal tissues, correlating with advanced disease stage, metastasis, and reduced patient survival. Mechanistically, OSCC exhibits global m⁶A hypomethylation, while YTHDF2 selectively destabilizes tumor-suppressive MTUS1/ATIP1 mRNA by recognizing m⁶A motifs in its 3' untranslated region. Functional studies using lentiviral overexpression and knockdown models demonstrated that YTHDF2 promotes tumor growth and mitochondrial dysfunction, whereas its suppression inhibits malignant behaviors and stabilizes MTUS1/ATIP1. Co-silencing MTUS1/ATIP1 reversed the anti-tumor effects of YTHDF2 depletion in vitro and in subcutaneous xenograft models. These findings establish YTHDF2 as a driver of OSCC progression through m⁶A-dependent suppression of MTUS1/ATIP1, linking mitochondrial dysregulation to tumorigenesis. Our study proposes therapeutic targeting of the YTHDF2-MTUS1/ATIP1 axis to improve OSCC management.

MTUS1/ATIP1; Mitochondrial dysfunction; N6-methyladenosine; Oral squamous cell carcinoma; YTHDF2.