APOL2 Stabilizes Ku80 to Confer NHEJ‐Mediated Radioresistance in Gastric Cancer
Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 protein levels to promote NHEJ repair, ultimately conferring radioresistance. Moreover, high-throughput screening identified formononetin (FN) as a small molecule capable of disrupting the APOL2-Ku80 interaction, thereby restoring radiosensitivity in GC cells. Our findings underscore the role of APOL2 in mediating radioresistance through Ku80 stabilization and highlight FN as a potential therapeutic agent to counteract radioresistance in GC treatment.
Authors
- Albino Bacolla (ORCID: https://orcid.org/0000-0003-0206-8423)
- Chunkai Zhang (ORCID: https://orcid.org/0000-0002-2207-0953)
- Yangchan Hu (ORCID: https://orcid.org/0009-0000-4923-2847)
- Yuke Zhong
- Yin Shi (ORCID: https://orcid.org/0000-0003-3858-8500)
- Dan Zu
- John A. Tainer (ORCID: https://orcid.org/0000-0003-1659-2429)
- Yixing Huang (ORCID: https://orcid.org/0000-0003-2627-3077)
- Guoyan Luo
- Xiangdong Cheng (ORCID: https://orcid.org/0000-0002-5099-490X)
- Hanyi He
- Zu Ye (ORCID: https://orcid.org/0000-0003-0846-7548)
- Mingcong Deng (ORCID: https://orcid.org/0000-0001-7411-6602)
- Shengfeng Xu (ORCID: https://orcid.org/0000-0002-5774-7549)
- Xiao Li (ORCID: https://orcid.org/0000-0002-9404-595X)
- Liang Chen (ORCID: https://orcid.org/0000-0002-1437-4308)
- Min Liu (ORCID: https://orcid.org/0000-0001-5183-1187)
- Jing Ji (ORCID: https://orcid.org/0000-0003-1004-8377)
- Yian Du
- Haidong Liu (ORCID: https://orcid.org/0000-0001-8519-3240)
- Yanhua He
- Weixin Wu
- Qimei Bao
- Fenghui Guan (ORCID: https://orcid.org/0000-0002-2756-5736)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Tianjin University (CN)
- Baylor College of Medicine (US)
- Chinese Academy of Sciences (CN)
- Zhejiang Cancer Hospital (CN)
- Hangzhou Medical College (CN)
- Hangzhou Cancer Hospital (CN)
- Zhejiang University of Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-09-15
- DOI
- https://doi.org/10.1002/advs.202506294
- Primary Topic
- Microbial metabolism and enzyme function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Zhejiang Province