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LSD1 suppresses invasion, migration and metastasis of luminal breast cancer cells via activation of GATA3 and repression of TRIM37 expression

Oncogene volume 38, pages 7017–7034 (2019)Cite this article

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Abstract

LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite functions remain largely elusive. By characterizing its role in luminal breast epithelial cells, here we show that inhibition of LSD1 by both genetic and pharmacological approaches increases their invasion and migration, whereas its inhibition by genetic approach, but not by pharmacological approach, impairs their proliferation/survival. Induced loss of LSD1 in luminal cells in a mouse model of luminal breast cancer, MMTV-PyMT, leads to a profound increase in lung metastasis. Mechanistically, LSD1 interacts with GATA3, a key luminal-specific transcription factor (TF), and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression. It also represses expression of TRIM37, a breast epithelial oncogene encoding a histone H2A ubiquitin ligase, and ELF5, a key TF gene for luminal progenitors and alveolar luminal cells. LSD1-loss also leads to reduced expression of several cell–cell adhesion genes (e.g., CDH1, VCL, CTNNA1), possibly via TRIM37-upregulation and subsequently TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the oncogenic program associated with LSD1-inhibition may be suppressed via TRIM37-inhibition.

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Data availability

The microarray expression profiling data has been deposited in the Genbank GEO database (http://www.ncbi.nlm.nih.gov/geo/) under accession code GSE95165.

References

  1. Shen H, Laird PW. Interplay between the cancer genome and epigenome. Cell. 2013;153:38–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.

    Article  CAS  PubMed  Google Scholar 

  3. Ahuja N, Easwaran H, Baylin SB. Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest. 2014;124:56–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119:941–53.

    Article  CAS  PubMed  Google Scholar 

  5. Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005;437:432–5.

    Article  CAS  PubMed  Google Scholar 

  6. Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell. 2009;138:660–72.

    Article  CAS  PubMed  Google Scholar 

  7. Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437:436–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wissmann M, Yin N, Muller JM, Greschik H, Fodor BD, Jenuwein T, et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat Cell Biol. 2007;9:347–53.

    Article  CAS  PubMed  Google Scholar 

  9. Garcia-Bassets I, Kwon YS, Telese F, Prefontaine GG, Hutt KR, Cheng CS, et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell. 2007;128:505–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, et al. p53 is regulated by the lysine demethylase LSD1. Nature. 2007;449:105–8.

    Article  CAS  PubMed  Google Scholar 

  11. Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet. 2009;41:125–9.

    Article  CAS  PubMed  Google Scholar 

  12. Lynch JT, Harris WJ, Somervaille TC. LSD1 inhibition: a therapeutic strategy in cancer? Expert Opin Ther Targets. 2012;16:1239–49.

    Article  CAS  PubMed  Google Scholar 

  13. Lim S, Janzer A, Becker A, Zimmer A, Schule R, Buettner R, et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 2010;31:512–20.

    Article  CAS  PubMed  Google Scholar 

  14. Serce N, Gnatzy A, Steiner S, Lorenzen H, Kirfel J, Buettner R. Elevated expression of LSD1 (Lysine-specific demethylase 1) during tumour progression from pre-invasive to invasive ductal carcinoma of the breast. BMC Clin Pathol. 2012;12:13.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res Treat. 2012;131:777–89.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang X, Lu F, Wang J, Yin F, Xu Z, Qi D, et al. Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells. Cell Rep. 2013;5:445–57.

    Article  CAS  PubMed  Google Scholar 

  17. Wu Y, Wang Y, Yang XH, Kang T, Zhao Y, Wang C, et al. The deubiquitinase USP28 stabilizes LSD1 and confers stem-cell-like traits to breast cancer cells. Cell Rep. 2013;5:224–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hu X, Li X, Valverde K, Fu X, Noguchi C, Qiu Y, et al. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc Natl Acad Sci USA. 2009;106:10141–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  20. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, et al. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 2010;29:1803–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu ZQ, Li XY, Hu CY, Ford M, Kleer CG, Weiss SJ. Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression. Proc Natl Acad Sci USA. 2012;109:16654–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007;9:201–9.

    Article  CAS  PubMed  Google Scholar 

  24. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006;127:1041–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, Vaillant F, et al. Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res. 2010;12:R21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Benner C, Konovalov S, Mackintosh C, Hutt KR, Stunnenberg R, Garcia-Bassets I. Decoding a signature-based model of transcription cofactor recruitment dictated by cardinal cis-regulatory elements in proximal promoter regions. PLoS Genet. 2013;9:e1003906.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Lee JY, Park MK, Park JH, Lee HJ, Shin DH, Kang Y, et al. Loss of the polycomb protein Mel-18 enhances the epithelial-mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancer. Oncogene. 2014;33:1325–35.

    Article  CAS  PubMed  Google Scholar 

  29. Choi YS, Chakrabarti R, Escamilla-Hernandez R, Sinha S. Elf5 conditional knockout mice reveal its role as a master regulator in mammary alveolar development: failure of Stat5 activation and functional differentiation in the absence of Elf5. Dev Biol. 2009;329:227–41.

    Article  CAS  PubMed  Google Scholar 

  30. Oakes SR, Naylor MJ, Asselin-Labat ML, Blazek KD, Gardiner-Garden M, Hilton HN, et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 2008;22:581–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li Q, Shi L, Gui B, Yu W, Wang J, Zhang D, et al. Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res. 2011;71:6899–908.

    Article  CAS  PubMed  Google Scholar 

  32. Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir JS, et al. TRIM37 is a new histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature. 2014;516:116–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Si W, Huang W, Zheng Y, Yang Y, Liu X, Shan L, et al. Dysfunction of the reciprocal feedback loop between GATA3- and ZEB2-nucleated repression programs contributes to breast cancer metastasis. Cancer Cell. 2015;27:822–36.

    Article  CAS  PubMed  Google Scholar 

  34. Yan W, Cao QJ, Arenas RB, Bentley B, Shao R. GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition. J Biol Chem. 2010;285:14042–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tao L, van Bragt MP, Li Z. A long-lived luminal subpopulation enriched with alveolar progenitors serves as cellular origin of heterogeneous mammary tumors. Stem Cell Rep. 2015;5:60–74.

    Article  CAS  Google Scholar 

  36. Tao L, van Bragt MPA, Laudadio E, Li Z. Lineage tracing of mammary epithelial cells using cell-type-specific Cre-expressing adenoviruses. Stem Cell Rep. 2014;2:770–9.

    Article  CAS  Google Scholar 

  37. Tao L, Xiang D, Xie Y, Bronson RT, Li Z. Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours. Nat Commun. 2017;8:14431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, et al. ELF5 drives lung metastasis in luminal breast cancer through recruitment of Gr1+ CD11b+ myeloid-derived suppressor cells. PLoS Biol. 2015;13:e1002330.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Network TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Article  CAS  Google Scholar 

  40. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486:346–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Asselin-Labat ML, Sutherland KD, Vaillant F, Gyorki DE, Wu D, Holroyd S, et al. Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14. Mol Cell Biol. 2011;31:4609–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ, et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 2008;13:141–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Choi HJ, Park JH, Park M, Won HY, Joo HS, Lee CH, et al. UTX inhibits EMT-induced breast CSC properties by epigenetic repression of EMT genes in cooperation with LSD1 and HDAC1. EMBO Rep. 2015;16:1288–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Feng J, Xu G, Liu J, Zhang N, Li L, Ji J, et al. Phosphorylation of LSD1 at Ser112 is crucial for its function in induction of EMT and metastasis in breast cancer. Breast Cancer Res Treat. 2016;159:443–56.

    Article  CAS  PubMed  Google Scholar 

  46. Mould DP, McGonagle AE, Wiseman DH, Williams EL, Jordan AM. Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date. Med Res Rev. 2015;35:586–618.

    Article  CAS  PubMed  Google Scholar 

  47. Maes T, Mascaro C, Tirapu I, Estiarte A, Ciceri F, Lunardi S, et al. ORY-1001, a potent and selective covalent KDM1A inhibitor, for the treatment of acute leukemia. Cancer Cell. 2018;33:495–511.

    Article  CAS  PubMed  Google Scholar 

  48. Woo AJ, Moran TB, Schindler YL, Choe SK, Langer NB, Sullivan MR, et al. Identification of ZBP-89 as a novel GATA-1-associated transcription factor involved in megakaryocytic and erythroid development. Mol Cell Biol. 2008;28:2675–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439:84–8.

    Article  CAS  PubMed  Google Scholar 

  50. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010;26:841–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, et al. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28:495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Stuart Orkin for the Lsd1L/L conditional knockout mouse line, and Drs. Alan Cantor, Hui Huang, and Andrew Woo (Boston Children’s Hospital) for help with gel filtration chromatography. This research was supported by Breakthrough Award from U.S. Department of Defense (W81XWH-15-1-0100), Pathway-to-Independence K99/R00 grant (CA126980) and R01 grant (CA222560) from NCI/NIH, Seed Grant (SG-0062-10) and Cancer Program Pilot Grant (DP-0137-13-00) from Harvard Stem Cell Institute, and Start-up Fund from Brigham and Women’s Hospital to ZL. This work was also supported by National Natural Science Foundation of China (NSFC31471356) and Jilin Province Science and Technology Development Project (20180101240JC, 20190701005GH) to XH.

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Authors and Affiliations

  1. School of Life Sciences, Jilin University, Changchun, China

    Xin Hu, Yu Zhang, Yue Jin & Youzhong Wan

  2. Division of Genetics, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    Xin Hu, Dongxi Xiang, Ying Xie, Luwei Tao & Zhe Li

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA, 02115, USA

    Luca Pinello & Guo-Cheng Yuan

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Hu, X., Xiang, D., Xie, Y. et al. LSD1 suppresses invasion, migration and metastasis of luminal breast cancer cells via activation of GATA3 and repression of TRIM37 expression. Oncogene 38, 7017–7034 (2019). https://doi.org/10.1038/s41388-019-0923-2

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