DataVXAdvanced SciencePaper
journal article·2025-11Open access

APOL2 Stabilizes Ku80 to Confer NHEJ‐Mediated Radioresistance in Gastric Cancer

Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A. Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Advanced Science· Volume 12· Issue 44
Publisher pageOpen full text
Source abstract

Abstract

Abstract 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.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Microbial metabolism and enzyme function · Cancer, Hypoxia, and Metabolism · Glutathione Transferases and Polymorphisms

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Life Sciences Tianjin University Tianjin 300100 China

Zhejiang Cancer Hospital Hangzhou Institute of Medicine (HIM) Chinese Academy of Sciences Hangzhou 310022 China

Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital) Hangzhou 310022 China

Key Laboratory of Prevention Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province Hangzhou 310022 China

Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer Zhejiang Cancer Hospital Hangzhou 310022 China

Hangzhou Medical College Hangzhou 310013 China

College of Pharmaceutical Science Zhejiang University of Technology Hangzhou 310014 China

Zhejiang University School of Medicine Hangzhou 310058 China

Human Genome Sequencing Center Baylor College of Medicine Houston TX 77030 USA

Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Funding

National Natural Science Foundation of China · Natural Science Foundation of Zhejiang Province

References (42)

Show source-provided references
1. 10.1371/journal.pgen.100944210.1371/journal.pgen.1009442 ↗
2. 10.1016/j.mrfmmm.2017.07.01110.1016/j.mrfmmm.2017.07.011 ↗
3. 10.1042/EBC2020000710.1042/EBC20200007 ↗
4. 10.1002/mco2.61310.1002/mco2.613 ↗
5. 10.3390/cells907166510.3390/cells9071665 ↗
6. 10.1038/s41467-022-28158-210.1038/s41467-022-28158-2 ↗
7. 10.1038/s41580-021-00405-210.1038/s41580-021-00405-2 ↗
8. 10.1038/s41392-021-00648-710.1038/s41392-021-00648-7 ↗
9. 10.1158/0008-5472.CAN-22-112410.1158/0008-5472.CAN-22-1124 ↗
10. 10.1016/j.dnarep.2020.10299210.1016/j.dnarep.2020.102992 ↗
11. 10.1155/2020/483496510.1155/2020/4834965 ↗
12. 10.1093/nar/gkad07610.1093/nar/gkad076 ↗
13. 10.1515/med-2023-075710.1515/med-2023-0757 ↗
14. 10.1186/s13045-023-01451-310.1186/s13045-023-01451-3 ↗
15. 10.1038/s41392-020-0150-x10.1038/s41392-020-0150-x ↗
16. 10.1177/153303382095940010.1177/1533033820959400 ↗
17. 10.1016/j.bbamcr.2020.11865910.1016/j.bbamcr.2020.118659 ↗
18. 10.1038/s41589-024-01704-310.1038/s41589-024-01704-3 ↗
19. 10.1634/theoncologist.2017-060910.1634/theoncologist.2017-0609 ↗
20. 10.2174/011386207325636323092920015710.2174/0113862073256363230929200157 ↗
21. Wang L. · J. Immunol. Res. · 2021 · 2021 · 1
22. 10.3390/v1309182110.3390/v13091821 ↗
23. 10.1016/j.dib.2021.10759610.1016/j.dib.2021.107596 ↗
24. 10.1093/nar/gkae14010.1093/nar/gkae140 ↗
25. 10.2147/JIR.S49612310.2147/JIR.S496123 ↗
26. 10.3390/genes1208114310.3390/genes12081143 ↗
27. 10.1016/j.redox.2021.10219410.1016/j.redox.2021.102194 ↗
28. 10.7150/ijbs.7096010.7150/ijbs.70960 ↗
29. 10.2147/OTT.S23933610.2147/OTT.S239336 ↗
30. 10.1007/s00432-021-03902-110.1007/s00432-021-03902-1 ↗
31. 10.3389/fimmu.2023.122939710.3389/fimmu.2023.1229397 ↗
32. 10.7150/ijbs.6941110.7150/ijbs.69411 ↗
33. 10.1038/s41568-023-00633-y10.1038/s41568-023-00633-y ↗
34. 10.1016/j.bbcan.2023.18890310.1016/j.bbcan.2023.188903 ↗
35. 10.6004/jnccn.2022.000810.6004/jnccn.2022.0008 ↗
36. 10.1001/jamaoncol.2022.012210.1001/jamaoncol.2022.0122 ↗
37. 10.1016/j.biopha.2022.11283610.1016/j.biopha.2022.112836 ↗
38. 10.1016/j.biopha.2024.11754510.1016/j.biopha.2024.117545 ↗
39. 10.1136/jmg.13.2.10310.1136/jmg.13.2.103 ↗
40. 10.1016/j.cub.2007.06.04410.1016/j.cub.2007.06.044 ↗
41. 10.1016/j.ccell.2019.11.00310.1016/j.ccell.2019.11.003 ↗
42. 10.1007/s12032-012-0360-310.1007/s12032-012-0360-3 ↗