High serum LDL promotes EMT and stemness through LDLR/FOXQ1/NF-κB1 pathway in epithelial ovarian cancer

Abstract

Epithelial ovarian cancer (EOC), the deadliest gynecological malignancy, is increasingly linked to dysregulated lipid metabolism. Nevertheless, the involvement of circulating low-density lipoprotein (LDL) in ovarian cancer progression remains controversial. Analyses of single-cell RNA sequencing and clinical data demonstrated a positive correlation between elevated LDL levels and EOC progression. Mechanistically, LDL internalized via LDL receptor (LDLR) enhanced epithelial-mesenchymal transition (EMT) and stemness in ovarian cancer cells, driven by the upregulation of the key transcription factor FOXQ1. Intriguingly, our investigations unveiled a novel transcriptional complex comprising FOXQ1/β-Catenin/ADNP. Both β-Catenin and ADNP interacted with FOXQ1 at the Forkhead domain, where FOXQ1 bound to the NF-κB1 gene promoter to enhance transcriptional activation. Notably, β-Catenin and ADNP were identified for the first time as competitive repressors within this regulatory axis. These findings were further corroborated in vivo using an ovarian cancer xenograft metastasis model, as well as in human pathological specimens, highlighting LDL-driven metastasis via FOXQ1 upregulation. Collectively, LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. Furthermore, we discover a novel transcriptional complex, where FOXQ1 acts as the central regulator while β-Catenin/ADNP serve as co-repressors. These insights suggest that modulating serum LDL levels or targeting FOXQ1 may offer promising strategies to curb ovarian cancer progression. LDL promotes ovarian cancer metastasis through LDLR/FOXQ1/NF-κB1 axis. High serum LDL uptake mediated by LDLR enhances EMT and stemness of ovarian cancer cells via upregulating FOXQ1 expression. Both β-Catenin and ADNP interact with FOXQ1 in the Forkhead domain (FH), also where FOXQ1 binds to NF-κB1 gene promoter to active its transcription, suggesting that β-Catenin and ADNP may act as competitive repressors in this novel transcriptional regulatory complex. Thus, controlling serum LDL levels and targeting FOXQ1 may be effective interventions for preventing metastasis in women with ovarian cancer.