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Abstract  Radiation resistance is a major cause of esophageal cancer relapse or metastasis. Transcriptional coactivator with PDZ binding domain (TAZ) is a final effector of the Hippo signaling pathway and plays critical roles in several types of cancer, but how it participates in the progression and radiation resistance of esophageal cancer remains unclear. Here, we revealed that TAZ was the strongest prognostic factor among Hippo pathway members. Overexpression of TAZ predicted poor outcome and adverse pathological features. In cell and animal models, TAZ facilitated cell proliferation, motility, and radiation resistance. Additionally, TAZ promoted expression of nonhomologous end joining (NHEJ)‐related genes, which are the main contributors to repair irradiation‐induced DNA breaks and result in radiation resistance. Amplification of the  TAZ  gene occurred in 2.5%‐3.2% of esophageal cancers. In addition, the CpG islands of the  TAZ  gene were demethylated in esophageal cancer under thymine DNA glycosylase (TDG) regulation. Knockdown of TDG inhibited cell growth, motility, and radiation resistance, which were overridden by TAZ overexpression. Collectively, these findings suggest that the TDG/TAZ/NHEJ axis is a critical player in esophageal cancer progression and radiation resistance, as well as a potential target for radiotherapy.

Thymine DNA glycosylase‐regulated TAZ promotes radioresistance by targeting nonhomologous end joining and tumor progression in esophageal cancer