REV7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX2

Abstract

Radiotherapy has been widely used for the clinical management of esophageal squamous cell carcinoma. However, radioresistance remains a serious concern that prevents the efficacy of ESCC radiotherapy. REV7, the structural subunit of eukaryotic DNA polymerase ζ, has multiple functions in bypassing DNA damage and modulating mitotic arrest in human cell lines. However, the expression and molecular function of REV7 in ESCC progression remains unclear. In this study, we first examined the expression of REV7 in clinical ESCC samples, and we found higher expression of REV7 in ESCC tissues compared to matched adjacent or normal tissues. Knockdown of REV7 resulted in decreased colony formation and increased apoptosis in irradiated Eca‐109 and TE‐1 cells coupled with decreased tumor weight in a xenograft nude mouse model post‐irradiation. Conversely, overexpression of REV7 resulted in the radioresistance in vitro and in vivo. Moreover, silencing of REV7 induced increased reactive oxygen species (ROS) levels post irradiation. To elucidate the underlying mechanism, proteomic analysis of REV7‐interacting proteins revealed that REV7 interacted with peroxiredoxin 2 (PRDX2), a well‐known antioxidant protein. Existence of REV7‐PRDX2 complex and its augmentation post irradiation were further validated by immunoprecipitation and immunofluorescence assays. REV7 knockdown significantly disrupted the presence of nuclear PRDX2 post irradiation, which resulted in oxidative stress. REV7‐PRDX2 complex also assembled onto DNA double strand breaks (DSBs), whereas REV7 knockdown evidently increased DSBs that were unmerged by PRDX2. Taken together, this study sheds light on REV7‐modulated radiosensitivity through interacting with PRDX2, which provides a novel target for ESCC radiotherapy.

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