Abstract 5293: Targeting the oncogenic RNA m6A reader YTHDF2 inhibits oral squamous cell carcinoma by preventing p53 degradation

Abstract Background: The N6-methyladenosine (m6A) RNA modification machinery has emerged as a critical modulator in cancer biology, however, the function of m6A “reader” proteins in oral squamous cell carcinoma (OSCC) is not fully understand. YTH domain family protein 2 (YTHDF2) is a prominent m6A-binding protein (m6A “reader”) that facilitates the degradation of methylated mRNAs and has been associated with tumorigenesis by targeting destabilization on clusters of tumor suppressor mRNAs. Nevertheless, the exact mechanism how YTHDF2 promotes OSCC proliferation and regulates p53 activity is in dire lack of elucidation. This study investigated the oncogenic role of YTHDF2 in OSCC and evaluated its potential as both a diagnostic biomarker and a therapeutic target. Methods: The mRNA and protein levels of YTHDF2 were examined in OSCC tissues, matched adjacent non-cancerous specimens as well as OSCC cell lines by quantitative real-time PCR (qRT-PCR) and Western blot. Furthermore, the TCGA-OSCC dataset were employed to evaluate YTHDF2 expression, its clinicopathological characteristics and prognostic value. Functional assays including proliferation, colony formation and wound-healing assays were performed to evaluate the oncogenic phenotypes in YTHDF2-depleted OSCC cell lines. The antitumor effects were examined in vitro via OSCC cell lines and patient-derived organoids (PDOs) derived from OSCC patients who received a selective YTHDF2 inhibitor. Results: YTHDF2 was remarkably up-regulated in OSCC tissues and cell lines compared with non-tumor tissues and normal cells, P < 0.001. Overexpression of YTHDF2 is correlated with OSCC development, progression and poor prognosis. YTHDF2 knockdown dramatically impaired OSCC cell proliferation, migration and tumorsphere formation. Functionally, YTHDF2 physically interacted with m6A-modified p53 transcripts and promoted their degradation. Inhibition of YTHDF2 significantly promoted the stability and protein expression of p53. YTHDF2 inhibitor impeded growth, migration, colony formation, tumorsphere and organoid development of cancer cells. Conclusions: Our results recognize YTHDF2 as an oncogenic m6A reader promoting the OSCC progression by increasing p53 mRNA degradation. Our findings indicate that YTHDF2 can be exploited therapeutically and tumor suppressively as a candidate antitumor approach in OSCC. Citation Format: Anitha Pandi, Vijayashree Priyadharsini Jayaseelan, Paramasivam Arumugam. Targeting the oncogenic RNA m6A reader YTHDF2 inhibits oral squamous cell carcinoma by preventing p53 degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5293.