The AEG-1-USP10-PARP1 axis confers radioresistance in esophageal squamous cell carcinoma via facilitating homologous recombination-dependent DNA damage repair

• Published in: Cancer letters Vol. 577; p. 216440
• Main Authors: Zhao, Xu, Ma, Yuan, Li, Jing, Sun, Xuanzi, Sun, Yuchen, Qu, Fengyi, Shi, Xiaobo, Xie, Yuchen, Liu, Siqi, Ma, Yanfang, Ji, Chao, Hu, Weibin, Che, Shaomin, Zhang, Xiaozhi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 28.11.2023
• Subjects: AEG-1; DNA double-strand breaks; Esophageal squamous cell carcinoma; Homologous recombination; Polyubiquitination; Esophageal squamous cell carcinoma; AEG-1; DNA double-strand breaks; Polyubiquitination; Homologous recombination
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2023.216440

Radiotherapy is the standard adjuvant treatment for esophageal squamous cell carcinoma (ESCC), yet radioresistance remains a major obstacle leading to treatment failure and unfavorable prognosis. Previous reports have demonstrated the involvement of astrocyte elevated gene-1 (AEG-1) in tumorigenesis and progression of multiple malignancies. Nevertheless, the precise role of AEG-1 in the radioresistance of ESCC remains elusive. Here, we unveiled a strong correlation between aberrant AEG-1 gene overexpression and malignant progression as well as adverse prognosis in ESCC patients. Moreover, both in vitro and in vivo investigations revealed that AEG-1 significantly alleviated irradiation-induced DNA damage and enhanced radiation resistance in ESCC cells. Mechanistically, AEG-1 recruited the deubiquitinase USP10 to remove the K48-linked polyubiquitin chains at the Lys425 of PARP1, thus preventing its proteasomal degradation. This orchestrated process facilitated homologous recombination-mediated DNA double-strand breaks (DSBs) repair, culminating in mitigated DNA damage and acquired radioresistance in ESCC cells. Notably, PARP1 overexpression reversed the radiosensitizing effect caused by AEG-1 deficiency. Collectively, these findings shed new light on the mechanism of ESCC radioresistance, providing potential therapeutic targets to enhance the efficacy of radiotherapy in ESCC. •High expression level of AEG-1 is associated with poor prognosis in ESCC.•AEG-1 alleviates irradiation-induced DNA damage and confers radioresistance in ESCC cells both in vitro and in vivo.•AEG-1 promotes the homologous recombination-mediated repair of irradiation-induced DNA double-strand breaks.•AEG-1 recruits USP10 to remove the K48-linked polyubiquitin chains at the Lys425 site of PARP1 to prevent its degradation.