期刊
ONCOGENE
卷 40, 期 43, 页码 6210-6222出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-02021-y
关键词
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资金
- Japan Society for the Promotion of Science: JSPS [21H03070, 19K18624, 17K16821, 16K11033, 16K11034]
- Uehara Memorial Foundation
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Japan Research Foundation for Clinical Pharmacology
- Yamaguchi Endocrine Disease Research Foundation
- Takeda Science Foundation
- Young Research Grant of Japanese Urological Association (JUA)
- Grants-in-Aid for Scientific Research [16K11033, 16K11034, 17K16821, 21H03070, 19K18624] Funding Source: KAKEN
Accumulating evidence supports the clinical benefit of chemoradiation therapy (CRT), but mechanisms in CRT-recurrent clones remain unclear. Aberrant BUB1B/BUBR1 expression was identified in CRT-recurrent bladder cancer cells, leading to excessive mutagenic DNA repair through nonhomologous end joining (NHEJ) and interaction with phosphorylated ATM. Inhibition of ATM abrogated CRT-resistant tumor growth, suggesting a novel approach to overcome CRT resistance.
There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.
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