Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents

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 compr...

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Published in:	Oncogene 2021-10, Vol.40 (43), p.6210-6222
Main Authors:	Komura, Kazumasa, Inamoto, Teruo, Tsujino, Takuya, Matsui, Yusuke, Konuma, Tsuyoshi, Nishimura, Kazuki, Uchimoto, Taizo, Tsutsumi, Takeshi, Matsunaga, Tomohisa, Maenosono, Ryoichi, Yoshikawa, Yuki, Taniguchi, Kohei, Tanaka, Tomohito, Uehara, Hirofumi, Hirata, Koichi, Hirano, Hajime, Nomi, Hayahito, Hirose, Yoshinobu, Ono, Fumihito, Azuma, Haruhito
Format:	Article
Language:	eng
Subjects:	Animals Ataxia Telangiectasia Mutated Proteins - metabolism Bladder cancer BUBR1 protein Cancer Cell Cycle Proteins - metabolism Cell Line, Tumor Chemoradiotherapy Chemotherapy CRISPR Deoxyribonucleic acid DNA DNA damage DNA Repair Drug resistance Drug Resistance, Neoplasm Drug therapy Forkhead Box Protein M1 - metabolism Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - radiation effects Genetic aspects Health aspects Humans Ionizing radiation Mice Neoplasm Transplantation Non-homologous end joining Phosphorylation Protein Serine-Threonine Kinases - metabolism Proteomics Pyridines - administration & dosage Pyridines - pharmacology Quinolines - administration & dosage Quinolines - pharmacology Radiotherapy Tumors Up-Regulation Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - pathology
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Summary:	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.
ISSN:	0950-9232 1476-5594