Forkhead box D1 promotes EMT and chemoresistance by upregulating lncRNA CYTOR in oral squamous cell carcinoma

Chemotherapy regimens containing cisplatin remain the first-line treatments for patients with oral squamous cell cancer (OSCC); however, the treatment effect is often transient because of chemoresistance and recurrence. Understanding the mechanisms of chemoresistance in OSCC might provide novel targetable vulnerabilities. In the present study, we revealed that Forkhead box D1 (FOXD1) is upregulated in OSCC and predicted poor prognosis. Moreover, ectopic expression of FOXD1 promoted, while silencing of FOXD1 inhibited, the epithelial-mesenchymal transition (EMT) and chemoresistance of OSCC, both in vitro and in vivo. Mechanistically, FOXD1 binds to the promoter of long non-coding RNA Cytoskeleton Regulator RNA (CYTOR) and activates its transcription. CYTOR then acts as a competing endogenous RNA to inhibit miR-1252–5p and miR-3148, thus upregulating lipoma preferred partner (LPP) expression. Importantly, the CYTOR/LPP axis was proven to be essential for FOXD1-induced EMT and chemoresistance in OSCC. These findings reveal a novel mechanism for the chemotherapy resistance of OSCC, suggesting that FOXD1 might be a potential prognostic marker and anti-resistance therapeutic target. •Forkhead box D1 (FOXD1) is upregulated in OSCC and predicted poor prognosis.•FOXD1 promotes the epithelial-mesenchymal transition and chemoresistance of OSCC.•FOXD1 binds to and activates the transcription of lncRNA CYTOR.•CYTOR acts as a ceRNA for miR-1252-5p and miR-3148 to upregulate LPP expression.•The CYTOR/LPP axis is essential for FOXD1-induced chemoresistance of OSCC.