LncRNA MIR4435-2HG-mediated succinylation of USF1 promotes its protein stability and induces epithelial-mesenchymal transition in HNSCC.

Tumor recurrence and metastasis remain the principal causes of mortality in patients with head and neck squamous cell carcinoma (HNSCC). However, the key molecular drivers underlying HNSCC progression and their regulatory mechanisms have not yet been fully elucidated. In this study, we investigated the biological role of the long noncoding RNA MIR4435-2HG in HNSCC. Integrated analyses across multiple public databases demonstrated that MIR4435-2HG is significantly upregulated in HNSCC and is closely associated with pathological T stage, clinical stage, and histological grade. Through further bioinformatic screening and functional validation, upstream transcription factor 1 (USF1) was identified as a critical downstream effector of MIR4435-2HG. Mechanistically, MIR4435-2HG directly interacts with USF1 and promotes its protein stability by facilitating USF1 succinylation, thereby enhancing tumor cell migration and invasion through the induction of epithelial - mesenchymal transition. Moreover, dual-luciferase reporter assays and RT-qPCR analyses revealed that CREB1 transcriptionally upregulates MIR4435-2HG expression, establishing a positive feedback regulatory circuit. Collectively, our findings demonstrate that MIR4435-2HG promotes USF1 succinylation and stabilization, leading to the formation of a MIR4435-2HG - USF1-AKT - CREB1 signalling loop that drives epithelial - mesenchymal transition and facilitates the invasive and metastatic potential of HNSCC cells.