DDX21 Enhances Radiosensitivity in Head and Neck Squamous Cell Carcinoma by Suppressing MK2‐Mediated DNA Damage Response

Radioresistance remains a significant challenge in the radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC). However, the biological factors that govern sensitivity to this therapy are not well-understood. The DEAD-box family is known for its role in genome stability, and inextricably linked to the radiotherapy resistance of tumors. This study found the role of the RNA helicase DDX21 in regulating radiosensitivity through extensive data mining. High DDX21 expression predicted improved survival after postoperative radiotherapy. Overexpression of DDX21 increased radiosensitivity in vitro and in vivo, whereas depletion promoted radioresistance. In vitro, DDX21 enhanced radiation-induced DNA damage, genomic instability, and apoptosis by binding MK2 and suppressing MK2 phosphorylation independently of p38 activity. Meanwhile MK2 inhibition restored and further augmented radiosensitivity in DDX21-deficient cells and xenografts by increasing DNA damage and apoptosis. Overall, DDX21 regulates radiosensitivity in HNSCC by suppressing MK2 signaling and modulating the radiation-induced DNA damage response. Its expression may serve as a potential biomarker associated with radiosensitivity, and MK2 inhibition offers a promising approach to overcome radioresistance in tumors with low DDX21 expression.