2. Academic Validation
  3. APOL2 Stabilizes Ku80 to Confer NHEJ-Mediated Radioresistance in Gastric Cancer

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

  • Adv Sci (Weinh). 2025 Sep 15:e06294. doi: 10.1002/advs.202506294.
Dan Zu 1 2 3,  Qimei Bao 2 3,  Hanyi He 2 4 5,  Yuke Zhong 2 3,  Mingcong Deng 6,  Yangchan Hu 2 7,  Chunkai Zhang 2 3,  Chen Liang 2 3,  Yixing Huang 3 8,  Haidong Liu 2 4 5,  Xiao Li 2 3,  Yanhua He 2 4 5,  Guoyan Luo 2,  Weixin Wu 2 3,  Fenghui Guan 1 2,  Shengfeng Xu 9,  Min Liu 10,  Albino Bacolla 10,  Ji Jing 2 4 5,  Yian Du 2 4 5,  John A Tainer 10,  Yin Shi 8,  Zu Ye 2 3 4 5 10,  Xiangdong Cheng 2 3 4 5
Affiliations

Affiliations

  • 1 School of Life Sciences, Tianjin University, Tianjin, 300100, China.
  • 2 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, China.
  • 3 Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, 310022, China.
  • 4 Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, 310022, China.
  • 5 Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
  • 6 Hangzhou Medical College, Hangzhou, 310013, China.
  • 7 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 8 Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 9 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 10 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
PMID: 40953331 DOI: 10.1002/advs.202506294
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

APOL2; Ku80; NHEJ; gastric cancer; ubiquitination.

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