Chromatin-Remodeling Complex SWI/SNF Controls Multidrug Resistance by Transcriptionally Regulating the Drug Efflux Pump ABCB1
| Autor: | Andres M. Lebensohn, Olivier Gevaert, Magali Champion, Jan E. Carette, Zahra Bahrami-Nejad, Rajat Rohatgi, Caleb D. Marceau, Branimir I. Sikic, Ramin Dubey |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research ATP Binding Cassette Transporter Subfamily B Transcription Genetic cells genetic processes ATP-binding cassette transporter macromolecular substances Biology Haploidy Chromatin remodeling Article 03 medical and health sciences medicine Humans Doxorubicin SMARCB1 DNA Helicases Nuclear Proteins SMARCB1 Protein Chromatin Assembly and Disassembly Molecular biology SWI/SNF Multiple drug resistance Gene Expression Regulation Neoplastic enzymes and coenzymes (carbohydrates) 030104 developmental biology Oncology Drug Resistance Neoplasm SMARCA4 Cancer research biological phenomena cell phenomena and immunity medicine.drug Genetic screen Transcription Factors |
| Zdroj: | Cancer research. 76(19) |
| ISSN: | 1538-7445 |
| Popis: | Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Doxorubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multidrug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1. Cancer Res; 76(19); 5810–21. ©2016 AACR. |
| Databáze: | OpenAIRE |
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