DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG

Platinum based drugs alone or in combination with 5FU and docetaxel are common regimen chemotherapeutics for the treatment of advanced OSCC. Chemoresistance is one of the major factors of treatment failure in OSCC. Human RNA helicase DDX3 plays an important role in cell proliferation, invasion, and metastasis in several neoplasms. The potential role of DDX3 in chemoresistance is yet to be explored. Enhanced cancer stem cells (CSCs) population significantly contributes to chemoresistance and recurrence. A recent study showed that m(6)A RNA regulates self-renewal and tumorigenesis property in cancer. In this study we found genetic (shRNA) or pharmacological (ketorolac salt) inhibition of DDX3 reduced CSC population by suppressing the expression of FOXM1 and NANOG. We also found that m(6)A demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased m(6)A methylation in FOXM1 and NANOG nascent transcript that contribute to chemoresistance. Here, we found DDX3 expression was upregulated in both cisplatin-resistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. In a patient-derived cell xenograft model of chemoresistant OSCC, ketorolac salt restores cisplatin-mediated cell death and facilitates a significant reduction of tumor burdens. Our work uncovers a critical function of DDX3 and provides a new role in m(6) demethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC.