HNRNPA2B1 promotes oral squamous cell carcinogenesis via m6A-dependent stabilization of FOXQ1 mRNA stability

Abstract

Oral squamous cell carcinoma (OSCC), as a common type of oral malignancy, has an unclear pathogenesis. N⁶ methyladenosine (m⁶A) is a reversible and dynamic process that participates in the modulation of cancer pathogenesis and development. As an m⁶A recognition protein (reader), heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) show abnormally high expression in cancers. Forkhead box Q1 (FOXQ1), an oncogenic transcription factor, controls multiple biological processes (e.g., embryonic development, cell differentiation, and apoptosis, impacting the initiation and progression of cancers by mediating signaling pathways together with epithelial-mesenchymal transition). Through the Cancer Genome Atlas database screening along with clinical and laboratory experiments, in head and neck squamous cell carcinoma, we found a correlation between HNRNPA2B1 and FOXQ1 gene expression, with shared m⁶A motifs between HNRNPA2B1 and FOXQ1 mRNA sequences. Silencing or overexpression of HNRNPA2B1 in OSCC cells affected the malignant phenotypes of OSCC cells in vitro, and depletion of HNRNPA2B1 retarded tumor growth in vivo. HNRNPA2B1 could bind to m⁶A-modified FOXQ1 mRNA to enhance its mRNA stability, resulting in up-regulation of FOXQ1 protein expression. To conclude, HNRNPA2B1 was upregulated in OSCC and enhanced OSCC cell malignant phenotypes by stabilizing m⁶A-modified FOXQ1 mRNA, eventually aggravating the malignancy and tumorigenicity of OSCC. This study accelerates the recognition of the potency of m⁶A modification in OSCC and paves the path for OSCC's targeted diagnosis and therapy.