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

Authors

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

Language

English

Publication Date

11-1-2025

Journal

Advanced Science

DOI

10.1002/advs.202506294

PMID

40953331

PMCID

PMC12667481

PubMedCentral® Posted Date

9-15-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Ku Autoantigen, Stomach Neoplasms, Radiation Tolerance, DNA End-Joining Repair, Cell Line, Tumor, Mice, Animals, DNA Breaks, Double-Stranded, APOL2, gastric cancer, Ku80, NHEJ, ubiquitination

Published Open-Access

yes

Recommended Citation

Zu, Dan; Bao, Qimei; He, Hanyi; et al., "APOL2 Stabilizes Ku80 to Confer NHEJ-Mediated Radioresistance in Gastric Cancer" (2025). Faculty, Staff and Student Publications. 6575.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6575