Metastasis: A metastatic switch

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Upregulation of SATB1 — a genome organizer that controls chromatin structure and the expression of multiple genomic loci — in breast cancer cells correlates with aggressive tumor phenotypes and shorter patient survival time.

When a tumour cell becomes metastatic it acquires many new abilities, such as motility, invasiveness and survival in the circulation; these are associated with a dramatically different gene expression profile. How do such global changes in gene expression occur? Do they accumulate one at a time, or could there be a single or a few events that cause widespread changes in gene expression and convert a mild-mannered tumour cell into a nasty one?

In their Nature paper, Terumi Kohwi-Shigematsu and colleagues report that SATB1, a genome organizer that controls chromatin structure and the expression of multiple genomic loci, is upregulated in aggressive breast cancer cells. Analysis of breast cancer cell lines and human tumour samples revealed that increased expression of SATB1 correlated with aggressive tumour phenotypes and shorter patient survival time.

Kohwi-Shigematsu's group found that RNA-interference-mediated knockdown of SATB1 in aggressive breast cancer cells altered the expression of 1,000 genes, restoring cell polarity in vitro and inhibiting tumour growth and metastasis in mice. Conversely, ectopic expression of SATB1 in non-aggressive cell lines resulted in a gene expression pattern frequently observed in highly aggressive breast tumours (a 'poor-prognosis signature') and caused these tumour cells to become invasive and metastatic in mice.

But what genes does SATB1 regulate, and how does it work? A comparison of gene expression profiles in several metastatic cell types before and after SATB1 knockdown showed that SATB1 controlled a quarter to a third of 'poor-prognosis genes', including genes that control adhesion, the cell cycle, the extracellular matrix, several signalling pathways, cell-cell junction formation and apoptosis.

The authors have previously shown that SATB1 functions at specific chromosome regions, folding DNA into dense loops that affect the binding of chromatin-modifying proteins and transcription factors; multiple epigenetic modifications and coordinated alterations in gene expression then occur in these regions. So, in a transformed cell that already has some cellular and genetic defects, upregulation of SATB1 might just be the switch that turns on (or off) groups of genes necessary to send the cell down the road to metastasis.

Kristine Novak

References

Han, H.-J., Russo, J., Kohwi, Y. & Kohwi-Shigematsu, T. SATB1 reprograms gene expression to promote breast tumor growth and metastasis. Nature 452, 187–193 (2008) | Article | PubMed |
Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nature Genet. 38, 1278-1288 (2006) | Article | PubMed |