title: Chromatin-Remodeling Complex SWI/SNF Controls Multidrug Resistance by Transcriptionally Regulating the Drug Efflux Pump ABCB1.
abstract: 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.
authors: Department of Biochemistry, Stanford University School of Medicine, Stanford, California. Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Ramin
authors: R
authors: Dubey
authors: Department of Biochemistry, Stanford University School of Medicine, Stanford, California. Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Andres M
authors: AM
authors: Lebensohn
authors: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California.
authors: Zahra
authors: Z
authors: Bahrami-Nejad
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California.
authors: Caleb
authors: C
authors: Marceau
authors: Stanford Center for Biomedical Informatics Research, Dept. of Medicine, Stanford, California.
authors: Magali
authors: M
authors: Champion
authors: Stanford Center for Biomedical Informatics Research, Dept. of Medicine, Stanford, California.
authors: Olivier
authors: O
authors: Gevaert
authors: Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors: Branimir I
authors: BI
authors: Sikic
authors: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California. rrohatgi@stanford.edu carette@stanford.edu.
authors: Jan E
authors: JE
authors: Carette
authors: Department of Biochemistry, Stanford University School of Medicine, Stanford, California. Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California. rrohatgi@stanford.edu carette@stanford.edu.
authors: Rajat
authors: R
authors: Rohatgi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006238:Haploidy; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D000071796:SMARCB1 Protein / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D004317:Doxorubicin; C084108:SMARCA4 protein, human; D004265:DNA Helicases