FOXF1 promotes ovarian cancer metastasis by facilitating HMGA2-mediated USP30-dependent S100A6 deubiquitination

Ovarian cancer is the most common type of gynecological malignant tumor, with the highest mortality rate among female genital malignant tumors. In this study, we initially identified forkhead box F1 (FOXF1) as a potential prognostic biomarker of ovarian cancer through bioinformatics analysis. FOXF1 expression was higher in ovarian cancer tissue samples and served as an unfavorable prognostic factor. In vitro and in vivo experiments demonstrated that FOXF1 enhanced ovarian cancer cell migration and tumor dissemination. Chromatin immunoprecipitation-polymerase chain reaction and luciferase assays revealed that FOXF1 bound directly to the high-mobility group AT-hook 2 (HMGA2) promoter and significantly induced its transcriptional activity. Subsequent co-immunoprecipitation and mass spectrometry analyses demonstrated that HMGA2 stabilized S100 calcium-binding protein A6 (S100A6) protein through recruitment of the deubiquitinase, ubiquitin-specific peptidase 30 (USP30), thereby inhibiting S100A6 degradation. Rescue experiments further illustrated that FOXF1 induced ovarian cancer cell mobility in an HMGA2/S100A6-dependent manner. Additionally, FOXF1, HMGA2, USP30, and S100A6 were clinically relevant in patients with ovarian cancer. This is the first study to reveal the molecular mechanisms underlying FOXF1-mediated ovarian cancer metastasis and demonstrate that FOXF1 represents a potential therapeutic target in patients with metastatic ovarian cancer.