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SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis

Abstract

Mechanisms underlying global changes in gene expression during tumour progression are poorly understood. SATB1 is a genome organizer that tethers multiple genomic loci and recruits chromatin-remodelling enzymes to regulate chromatin structure and gene expression. Here we show that SATB1 is expressed by aggressive breast cancer cells and its expression level has high prognostic significance (P < 0.0001), independent of lymph-node status. RNA-interference-mediated knockdown of SATB1 in highly aggressive (MDA-MB-231) cancer cells altered the expression of >1,000 genes, reversing tumorigenesis by restoring breast-like acinar polarity and inhibiting tumour growth and metastasis in vivo. Conversely, ectopic SATB1 expression in non-aggressive (SKBR3) cells led to gene expression patterns consistent with aggressive-tumour phenotypes, acquiring metastatic activity in vivo. SATB1 delineates specific epigenetic modifications at target gene loci, directly upregulating metastasis-associated genes while downregulating tumour-suppressor genes. SATB1 reprogrammes chromatin organization and the transcription profiles of breast tumours to promote growth and metastasis; this is a new mechanism of tumour progression.

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Figure 1: SATB1 expression in breast cancer is associated with poor prognosis.
Figure 2: SATB1 depletion restores cell polarity and reduces aggressive phenotypes of MDA-MB-231 cells in vitro.
Figure 3: SATB1 is necessary for lung colonization and tumour growth.
Figure 4: Ectopic expression of SATB1 in SKBR3 cells induced tumour growth, intravasation and lung colonization.
Figure 5: Global changes in expression profiles on SATB1 expression.
Figure 6: SATB1 defines the epigenetic status of target genes.

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Primary accessions

Gene Expression Omnibus

Data deposits

The expression data set is on the GEO website under accession number GSE5417.

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Acknowledgements

We thank J. W. Gray and M. Stamfers for providing some of the cell lines, M. J. Bissell, C. W. Roberts, J. A. Nickerson and S. A. Krauss for critical reading of the manuscript and useful suggestions, K. Novak and M. Kohwi for help in manuscript preparation, and R. Simon and M. Falduto for assisting expression microarray data analysis. This work was supported by a National Institute of Health grant to T.K.-S. and also by University of California Breast Cancer Research Program at its initial stage.

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Correspondence to Yoshinori Kohwi or Terumi Kohwi-Shigematsu.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-7 with Legends and Supplementary Tables 1-4. These show additional information on clinical evaluation of SATB1 in breast cancer, in vitro/in vivo analyses on the effect of SATB1 on tumor growth and metastasis, expression microarray/pathway analyses of SATB1’s target genes, and urea-ChIP data for other target and non-target genes. (PDF 5803 kb)

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Han, HJ., Russo, J., Kohwi, Y. et al. SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature 452, 187–193 (2008). https://doi.org/10.1038/nature06781

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