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

Jan 25, 2020Apoptosis : an international journal on programmed cell death

DDX3 may affect cisplatin resistance in oral cancer by changing RNA modification of FOXM1 and NANOG

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Abstract

DDX3 expression was upregulated in cisplatin-resistant OSCC lines and tumors compared to sensitive counterparts.

Inhibition of DDX3, either genetically or pharmacologically, reduced the population of cancer stem cells by suppressing key genes associated with self-renewal.
The enzyme ALKBH5, regulated by DDX3, was found to decrease methylation on specific RNA transcripts linked to chemoresistance.
Enhanced cancer stem cell populations contribute significantly to treatment resistance and recurrence in advanced oral squamous cell carcinoma (OSCC).
In a patient-derived model of chemoresistant OSCC, treatment with ketorolac salt restored sensitivity to cisplatin and reduced tumor size.
The findings suggest a potential new therapeutic avenue by combining ketorolac salt with cisplatin for advanced OSCC.

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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 mA 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 mA demethylase ALKBH5 is directly regulated by DDX3 which leads to decreased mA 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 mdemethylation of RNA. A combination regimen of ketorolac salt with cisplatin deserves further clinical investigation in advanced OSCC. 6 6 6 6

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

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