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Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes

Nature Cancer volume 1, pages 909–922 (2020)Cite this article

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Abstract

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical BAF (cBAF)-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiological and biochemical consequences of ARID1A/ARID1B loss. In double-knockout liver and skin, aggressive carcinogenesis followed dedifferentiation and hyperproliferation. In double-mutant endometrial cancer, add-back of either induced senescence. Biochemically, residual cBAF subcomplexes resulting from loss of ARID1 scaffolding were unexpectedly found to disrupt a polybromo-containing BAF (pBAF) function. Of 69 mutations in the conserved scaffolding domains of ARID1 proteins observed in human cancer, 37 caused complex disassembly, partially explaining their mutation spectra. ARID1-less, cBAF-less states promote carcinogenesis across tissues, and suggest caution against paralog-directed therapies for ARID1-mutant cancer.

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Fig. 1: Loss of both ARID1A and ARID1B in the liver leads to impaired liver function, increased cell growth and tumor formation.
Fig. 2: Loss of ARID1A and ARID1B in the liver leads to hyperproliferation and dedifferentiation.
Fig. 3: Hyperproliferation and dedifferentiation are immediate effects after ARID1A/1B loss.
Fig. 4: UBC-CreER-induced DKO mice develop invasive SCCs.
Fig. 5: Loss of both ARID1A and ARID1B proteins in endometrial cancer cells is essential for transformation and proliferation.
Fig. 6: Residual cBAF complexes secondary to ARID1A/B loss do not possess neofunctionality.
Fig. 7: The presence of residual cBAF subcomplexes is associated with pBAF disruption.
Fig. 8: Biological consequences of 69 ARID1A/1B mutations in cancer.

Data availability

All sequencing data have been deposited in the Gene Expression Omnibus with the accession nos. GSE147664 for mRNA-seq and GSE140183 for ChIP–seq. Source data are provided with this paper. All other data supporting the findings of the present study are available from the corresponding author on reasonable request.

References

  1. Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Ronan, J. L., Wu, W. & Crabtree, G. R. From neural development to cognition: unexpected roles for chromatin. Nat. Rev. Genet. 14, 347–359 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Son, E. Y. & Crabtree, G. R. The role of BAF (mSWI/SNF) complexes in mammalian neural development. Am. J. Med. Genet. C Semin. Med. Genet. 166C, 333–349 (2014).

    Article  PubMed  CAS  Google Scholar 

  5. Staahl, B. T. & Crabtree, G. R. Creating a neural specific chromatin landscape by npBAF and nBAF complexes. Curr. Opin. Neurobiol. 23, 903–913 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Wang, W. et al. Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J. 15, 5370–5382 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gatchalian, J. et al. A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells. Nat. Commun. 9, 5139 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Wang, X. et al. BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors. Nat. Commun. 10, 1881 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Mashtalir, N. et al. Modular organization and assembly of SWI/SNF family chromatin remodeling complexes. Cell 175, 1272–1288 e1220 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Raab, J. R., Resnick, S. & Magnuson, T. Genome-wide transcriptional regulation mediated by biochemically distinct swi/snf complexes. PLoS Genet. 11, e1005748 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592–601 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Biegel, J. A., Busse, T. M. & Weissman, B. E. SWI/SNF chromatin remodeling complexes and cancer. Am. J. Med. Genet. C Semin. Med. Genet. 166C, 350–366 (2014).

    Article  PubMed  CAS  Google Scholar 

  13. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Sun, X. et al. Arid1a has context-dependent oncogenic and tumor suppressor functions in liver cancer. Cancer Cell 33, 151–152 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bitler, B. G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Fukumoto, T. et al. Repurposing pan-HDAC Inhibitors for ARID1A-mutated ovarian cancer. Cell Rep. 22, 3393–3400 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lissanu Deribe, Y. et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat. Med. 24, 1047–1057 (2018).

    Article  CAS  PubMed  Google Scholar 

  19. McDonald, E. R. 3rd et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170, 577–592 e510 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Michel, B. C. et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat. Cell Biol. 20, 1410–1420 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ogiwara, H. et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers. Cancer Cell 35, 177–190 e178 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Williamson, C. T. et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 7, 13837 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu, C. et al. Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat. Commun. 9, 3212 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Shen, J. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat. Med. 24, 556–562 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Viswanathan, S. R. et al. Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer. Nat. Genet. 50, 937–943 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kelso, T. W. R. et al. Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. eLife. 6, e30506 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Coatham, M. et al. Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas. Mod. Pathol. 29, 1586–1593 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, X. et al. Suppression of the SWI/SNF component Arid1a Promotes mammalian regeneration. Cell Stem Cell 18, 456–466 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Celen, C. et al. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. eLife 6, e25730 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Oba, A. et al. ARID2 modulates DNA damage response in human hepatocellular carcinoma cells. J. Hepatol. 66, 942–951 (2017).

    Article  CAS  PubMed  Google Scholar 

  33. Zhao, H. et al. ARID2: a new tumor suppressor gene in hepatocellular carcinoma. Oncotarget 2, 886–891 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jiang, H. et al. Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis. Proc. Natl Acad. Sci. USA 117, 4770–4780 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, M. et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat. Genet. 43, 828–829 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kirmitzoglou, I. & Promponas, V. J. LCR-eXXXplorer: a web platform to search, visualize and share data for low complexity regions in protein sequences. Bioinformatics 31, 2208–2210 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Santen, G. W. et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin–Siris syndrome. Nat. Genet. 44, 379–380 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Tsurusaki, Y. et al. Mutations affecting components of the SWI/SNF complex cause Coffin–Siris syndrome. Nat. Genet. 44, 376–378 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Sausen, M. et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat. Genet. 45, 12–17 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Jiao, Y. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45, 1470–1473 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Holz-Schietinger, C., Matje, D. M., Harrison, M. F. & Reich, N. O. Oligomerization of DNMT3A controls the mechanism of de novo DNA methylation. J. Biol. Chem. 286, 41479–41488 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jurkowska, R. Z. et al. Oligomerization and binding of the Dnmt3a DNA methyltransferase to parallel DNA molecules: heterochromatic localization and role of Dnmt3L. J. Biol. Chem. 286, 24200–24207 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nemeth, A., Guibert, S., Tiwari, V. K., Ohlsson, R. & Langst, G. Epigenetic regulation of TTF-I-mediated promoter-terminator interactions of rRNA genes. EMBO J. 27, 1255–1265 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhu, H. et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat. Genet. 42, 626–630 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank C. Kadoch, S. McBrayer, J. Wu, J. Xu, L. Banaszynski, X. Liu and S. Wang for constructive comments on the manuscript; C. Lewis and J. Shelton for histopathology; Proteomics Core at UTSW (A. Lemoff) for MS; and the CRI Sequencing Core (J. Xu) for genomics. Funding sources: NIH R03ES026397-01 (to T.W.), CPRIT RP150596 (to T.W.), CPRIT RP170267 (to H.Z.), NIH/NIDDK R01DK111588 (to H.Z.) and Stand Up To Cancer Innovative Research Grant (no. SU2C-AACR-IRG 10-16 to H.Z.).

Author information

Authors and Affiliations

  1. Children’s Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Zixi Wang, Yuemeng Jia, Jen-Chieh Chuang, Xuxu Sun, Yu-Hsuan Lin, Cemre Celen, Lin Li, Fang Huang, Xin Liu & Hao Zhu

  2. Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Kenian Chen & Tao Wang

  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Diego H. Castrillon

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Contributions

Z.W. and H.Z. conceived the project, performed the experiments and wrote the manuscript. J-C.C., X.S., Z.W., L.L. and C.C. created and analyzed the mouse models. K.C., Y.J., X.S., F.H., X.L. and T.W. generated and analyzed genomic data. Y.-H.L. assisted with the histology analysis. D.H.C edited the manuscript and provided assistance with disease models.

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Correspondence to Hao Zhu.

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Competing interests

At the time of publication, H.Z. owned Ionis Pharmaceuticals stock worth less than $US10,000 and has active collaboration with Alnylam Pharmaceuticals and Twenty-Eight Seven Therapeutics. The remaining authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Loss of both ARID1A and ARID1B in the liver leads to impaired liver function.

a Kaplan-Meier survival curve of WT and DKO mice within the first month of life. b Body weight of WT and DKO mice at the age of 1 month (n = 12 and 8 mice). c-g. Liver function analysis using plasma (n = 6 and 5 mice for the Arid1af/f group; 6 and 6 for the Arid1bf/f group; 8 and 8 for the Arid1af/f; Arid1bf/f group). h Gross inspection of plasma from AKO, BKO and DKO and their corresponding WT mice. i IHC staining of ARID1A and ARID1B on WT and DKO liver sections. j Western blot showing ARID1A and ARID1B protein levels in WT and DKO livers. k Quantification of Western blot data in j (n = 6 and 6 mice for each group). Data are presented as mean ± s.d. (b-g,k). Statistical significance was determined by two-tailed unpaired Student’s t-tests with Welch’s correction (b-g, k).

Source data

Extended Data Fig. 2 AAV mediated deletion of ARID1A and ARID1B in the liver leads to organ failure.

a Gross inspection of plasma from mice injected with AAV-GFP or AAV-Cre. b-f. Liver function tests of Arid1af/f; Arid1bf/f mice injected with AAV-GFP or AAV-Cre (n = 10 and 10 mice for AST; 9 and 10 for ALT; 9 and 11 for TBIL; 10 and 11 for ALKP; 9 and 11 for Albumin. Data are presented as mean ± s.d. Statistical significance was determined by two-tailed unpaired Student’s t-tests with Welch’s correction). g Representative genome browser tracks showing ARID1A binding to the promoter or enhancer regions of differentiation and Cytochrome P450 genes in liver. h IHC staining of EpCAM and CK-19 on AAV-Cre liver sections.

Source data

Extended Data Fig. 3 cBAF subunit levels showed limited to no decrease in ARID1-less cells or DKO livers.

a Western blot analysis of cBAF subunit levels in WT and ARID1-less H2.35 cells (n = 3 and 3 independent clones). b Colony formation assay for control and ARID1-less H2.35 cells. 0.1 million H2.35 cells were seeded in each well of 6-well plate and cultured for 10 days in the presence of Dox. c Western blot analysis of cBAF subunit levels in WT and DKO livers (n = 6 and 6 mice). Same batch of western blots/protein samples as in Extended Data Fig. 1j. d Quantification of western blot data in c (Data are presented as mean ± s.d. Statistical significance was determined by two-tailed unpaired Student’s t-tests with Welch’s correction).

Source data

Extended Data Fig. 4 ChIP-seq analysis of SWI/SNF complexes binding to genomic DNA in control and ARID1-less H2.35 cells.

a Expression of Ty1 tagged BRD9 and Brg1 in WT and ARID1-less H2.35 cells. BRD9 expression was only examined using the Ty1 antibody due to the lack of a commercial anti-mouse BRD9 antibody. b Heatmap displaying ChIP-seq peaks of intact SWI/SNF complexes in WT H2.35 cells. ARID1A, ARID1B, and BAF45d peaks were used to represent cBAF, ARID2 for pBAF, BRD9 for ncBAF, and Brg1 for all BAF complexes. 3000 bp upstream and downstream of peak centers are shown in this figure (n = 2 independent ChIP experiments for each protein). c Venn diagram showing the shared and unique binding loci among three types of BAF complexes from ChIP-seq data. d Comparison of BRD9 occupancies in control and ARID1-less cells. Heatmap and the corresponding averaged peak map and Venn diagram are shown (n = 2 and 2 independent ChIP experiments). e Representative genome browser tracks showing that ncBAF binding was unaffected in ARID1-less cells (BRD9 peaks in ARID1-less cells).

Source data

Extended Data Fig. 5 Mapping of domains, residues, and mutations responsible for ARID1A’s scaffolding role.

a Multiple sequence alignment of ARID1A protein C-terminal regions from human, mouse, dog, bovine, rabbit, chicken, clawed frog, and zebrafish showing two conserved ARID1 scaffolding domains (ASD1 and ASD2). b Secondary structure prediction of ARID1A using LCR-eXXXplorer server. Regions with a score lower than 0.5 (shown as a cyan line for the IUPRED score and a red line for the ANCHOR score) are likely well-folded globular domains. c Alanine scans within ASD1 of ARID1A and IP experiments to assess residues for cBAF subunit interactions. The indicated two residues were mutated to alanine in each construct. d IP experiments showing the influence of ARID1A missense mutations within ASD2 on BAF subunit interactions. e Western blot showing the influence of ARID1A hotspot missense mutations on protein stability in H2.35 cells. f Western blot showing the influence of ARID1A truncations on protein stability in H2.35 cells.

Source data

Supplementary information

Reporting summary

Supplementary Table

Supplementary Tables 1 and 2.

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Wang, Z., Chen, K., Jia, Y. et al. Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes. Nat Cancer 1, 909–922 (2020). https://doi.org/10.1038/s43018-020-00109-0

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