RUNX2 Isoform II Protects Cancer Cells from Ferroptosis by Promoting PRDX2 Expression in Oral Squamous Cell Carcinoma

Ferroptosis is a distinct iron-dependent programmed cell death and plays important roles in tumor suppression. However, the regulatory mechanisms of ferroptosis need further exploration. RUNT-related transcription factor 2 (RUNX2), a transcription factor, is essential for osteogenesis. RUNX2 has two types of transcripts produced by two alternative promoters. In the present study, we surprisingly find that RUNX2 isoform II is a novel ferroptosis suppressor. RUNX2 isoform II can bind to the promoter of peroxiredoxin-2 (PRDX2), a ferroptosis inhibitor, and activate its expression. Knockdown of RUNX2 isoform II suppresses cell proliferationin vitroand tumorigenesisin vivoin oral squamous cell carcinoma (OSCC). Interestingly, homeobox A10 (HOXA10), an upstream positive regulator of RUNX2 isoform II, is required for the inhibition of ferroptosis through the RUNX2 isoform II/PRDX2 pathway. Consistently, RUNX2 isoform II is overexpressed in OSCC, and associated with OSCC progression and poor prognosis. Collectively, OSCC cancer cells can up-regulate RUNX2 isoform II to inhibit ferroptosis and facilitate tumorigenesis through the novel HOXA10/RUNX2 isoform II/PRDX2 pathway.