Targeting ARID1A-mutant colorectal cancer: depletion of ARID1B increases radiosensitivity and modulates DNA damage response

The SWI/SNF chromatin remodeling complex has been found mutated in a wide range of human cancers, causing alterations in gene expression patterns, proliferation and DNA damage response that have been linked to poor clinical prognosis. Here, we investigated weather knockdown of ARID1B, one of two mut...

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Bibliographic Details
Published in:Scientific reports 2019-12, Vol.9 (1), p.18207-9, Article 18207
Main Authors: Niedermaier, B, Sak, A, Zernickel, E, Xu, Shan, Groneberg, M, Stuschke, M
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Cancer
Cell Line, Tumor
Chemoradiotherapy - methods
Chromatin Assembly and Disassembly - drug effects
Chromatin Assembly and Disassembly - genetics
Chromatin Assembly and Disassembly - radiation effects
Chromatin remodeling
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - therapy
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded - radiation effects
DNA damage
DNA Repair - drug effects
DNA Repair - genetics
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
Fibroblasts
Gene expression
Gene Knockdown Techniques
Homologous recombination
Homologous recombination repair
Humans
Ionizing radiation
Medical prognosis
Mutation
Rad51 Recombinase - metabolism
Radiation therapy
Radiation Tolerance - genetics
Radiosensitivity
RNA, Small Interfering - metabolism
siRNA
SWI/SNF complex
Transcription Factors - antagonists & inhibitors
Transcription Factors - genetics
Tumor cell lines
Tumor Stem Cell Assay
Tumor Suppressor p53-Binding Protein 1 - metabolism
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Summary:The SWI/SNF chromatin remodeling complex has been found mutated in a wide range of human cancers, causing alterations in gene expression patterns, proliferation and DNA damage response that have been linked to poor clinical prognosis. Here, we investigated weather knockdown of ARID1B, one of two mutually exclusive subunits within the SWI/SNF complex, can sensitize colorectal cancer cell lines mutated in the other subunit, ARID1A, to ionizing radiation (IR). ARID1A-mutated colorectal cancer (CRC) cell lines are selectively sensitized to IR after siRNA mediated ARID1B depletion, as measured by clonogenic survival. This is characterized by a decrease in the surviving cell fraction to 87.3% ± 2.1%, 86.0% ± 1.1% and 77.2% ± 1.5% per 1 Gy compared with control siRNA exposed cells in the dose range of 0-6 Gy for the LS180, RKO and SW48 lines, respectively (p 
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-54757-z