CircRHBDD1(4,5) drives malignant progression of oral squamous cell carcinoma by enhancing DKK1 mRNA stability through facilitating m6A-dependent IGF2BP2 binding.

Oral squamous cell carcinoma (OSCC) is a malignant tumor arising from the oral mucosa and is highly prevalent in Southeast Asia and the Pacific region. Recurrence and metastasis significantly contribute to poor clinical outcomes, highlighting the importance of understanding the underlying molecular mechanisms. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs, have emerged as key regulators of tumor development and progression. However, their roles in OSCC remain largely unexplored. In this study, we identified for the first time that circRHBDD1(4,5) (hsa_circ_0058493, a 656-nt circRNA generated by back-splicing of exons 4 and 5 of the RHBDD1 gene) is markedly upregulated in OSCC and promotes tumor cell proliferation, invasion, and metastasis. Mechanistically, circRHBDD1(4,5) functions as a molecular scaffold that brings IGF2BP2 and DKK1 mRNA into close proximity, thereby facilitating the m6A-dependent recognition of DKK1 mRNA by IGF2BP2, which is mediated by WTAP. This interaction enhances DKK1 mRNA stability, leading to increased DKK1 expression and subsequent activation of the PI3K-AKT signaling pathway, thereby driving the malignant progression in OSCC. Collectively, our findings highlight the critical role of the circRHBDD1(4,5)/IGF2BP2/DKK1 axis in OSCC pathogenesis and provide a potential foundation for developing novel targeted therapeutic strategies.