Chromatin Accessibility Underlies Synthetic Lethality of SWI/SNF Subunits in ARID1A-mutant Cancers

Overview

Journal Elife

Specialty Biology

Date 2017 Oct 3

PMID 28967863

Citations 95

Authors

Timothy W R Kelso

Devin K Porter

Maria Luisa Amaral

Maxim N Shokhirev

Christopher Benner

Diana C Hargreaves

Affiliations

Soon will be listed here.

Abstract

ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including . We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.

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References

de Dieuleveult M, Yen K, Hmitou I, Depaux A, Boussouar F, Bou Dargham D . Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells. Nature. 2016; 530(7588):113-6. PMC: 4871117. DOI: 10.1038/nature16505. View

Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S . A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell. 1994; 77(2):261-71. DOI: 10.1016/0092-8674(94)90318-2. View

Hah N, Murakami S, Nagari A, Danko C, Kraus W . Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 2013; 23(8):1210-23. PMC: 3730096. DOI: 10.1101/gr.152306.112. View

Chandler R, Damrauer J, Raab J, Schisler J, Wilkerson M, Didion J . Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. Nat Commun. 2015; 6:6118. PMC: 4308813. DOI: 10.1038/ncomms7118. View

Huang Z, Li J, Sachs L, Cole P, Wong J . A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for transcription. EMBO J. 2003; 22(9):2146-55. PMC: 156091. DOI: 10.1093/emboj/cdg219. View

Kwon H, Imbalzano A, Khavari P, Kingston R, Green M . Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature. 1994; 370(6489):477-81. DOI: 10.1038/370477a0. View

Lakshminarasimhan R, Andreu-Vieyra C, Lawrenson K, Duymich C, Gayther S, Liang G . Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells. Cancer Lett. 2017; 401:11-19. PMC: 5645058. DOI: 10.1016/j.canlet.2017.04.040. View

Baldus S, Kort E, Schirmacher P, Dienes H, Resau J . Quantification of MET and hepatocyte growth factor/scatter factor expression in colorectal adenomas, carcinomas and non-neoplastic epithelia by quantitative laser scanning microscopy. Int J Oncol. 2007; 31(1):199-204. View

Kadoch C, Hargreaves D, Hodges C, Elias L, Ho L, Ranish J . Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013; 45(6):592-601. PMC: 3667980. DOI: 10.1038/ng.2628. View

10.

Cote J, Quinn J, Workman J, Peterson C . Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science. 1994; 265(5168):53-60. DOI: 10.1126/science.8016655. View

11.

Wang X, Nagl N, Wilsker D, Van Scoy M, Pacchione S, Yaciuk P . Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem J. 2004; 383(Pt 2):319-25. PMC: 1134073. DOI: 10.1042/BJ20040524. View

12.

Wiegand K, Shah S, Al-Agha O, Zhao Y, Tse K, Zeng T . ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010; 363(16):1532-43. PMC: 2976679. DOI: 10.1056/NEJMoa1008433. View

13.

Larsen C, Dashwood R . (-)-Epigallocatechin-3-gallate inhibits Met signaling, proliferation, and invasiveness in human colon cancer cells. Arch Biochem Biophys. 2010; 501(1):52-7. PMC: 2916072. DOI: 10.1016/j.abb.2010.03.017. View

14.

Ogiwara H, Ui A, Otsuka A, Satoh H, Yokomi I, Nakajima S . Histone acetylation by CBP and p300 at double-strand break sites facilitates SWI/SNF chromatin remodeling and the recruitment of non-homologous end joining factors. Oncogene. 2011; 30(18):2135-46. DOI: 10.1038/onc.2010.592. View

15.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

16.

Chandler R, Brennan J, Schisler J, Serber D, Patterson C, Magnuson T . ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF. Mol Cell Biol. 2012; 33(2):265-80. PMC: 3554127. DOI: 10.1128/MCB.01008-12. View

17.

Arner E, Daub C, Vitting-Seerup K, Andersson R, Lilje B, Drablos F . Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science. 2015; 347(6225):1010-4. PMC: 4681433. DOI: 10.1126/science.1259418. View

18.

Euskirchen G, Auerbach R, Davidov E, Gianoulis T, Zhong G, Rozowsky J . Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches. PLoS Genet. 2011; 7(3):e1002008. PMC: 3048368. DOI: 10.1371/journal.pgen.1002008. View

19.

Li Y, Wang J, Gao X, Han W, Zheng Y, Xu H . c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation. PLoS One. 2014; 9(11):e113186. PMC: 4245100. DOI: 10.1371/journal.pone.0113186. View

20.

Wang W, Cote J, Xue Y, Zhou S, Khavari P, Biggar S . Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 1996; 15(19):5370-82. PMC: 452280. View