Genome organiser rules the metastasis roost

A 'genome organiser' by the name of SATB1 promotes aggressive breast cancer by altering the behaviour of more than 1000 other genes in tumour cells, US researchers report.

SATB1, or special AT-rich binding protein 1, is known to be essential for the proper development of T cells, but now it seems it is also necessary for breast cancer cells to become metastatic.

Terumi Kohwi-Shigematsu and colleagues, including her husband Yoshinori Kohwi, from the Lawrence Berkeley National Laboratory at the University of California, were the first to clone SATB1 in 1992 and have been studying it ever since.

They have previously found that SATB1 is a 'genome organiser', running a regulatory network of gene expression by recruiting chromatin remodelling enzymes and transcription factors to genomic DNA.

The protein binds to base-unpairing regions or BURs, a class of DNA sequences that have a tendency to unwind or pop open, and sets about refolding chromatin to regulate gene expression. It is highly expressed in thymocytes, the precursors of T cells, and therefore is essential to the development of the immune system.

Now, the team has found that once SATB1 is expressed in breast cancer cells it reprograms the expression of over 1000 genes and induces metastasis.

Writing in the March 13 issue of Nature, the researchers found that SATB1 upregulated many genes known to have important functions in promoting metastasis, including metastasin, VEGFB and TGF-B1, as well as genes involved in epidermal growth factor signalling, including HER2. They also found that SATB1 represses metastasis suppressor genes.

Knocking down SATB1 in highly aggressive breast cancer cells by RNAi not only reverses metastatic phenotypes and returns cells to their normal shape but also inhibits tumour growth, the researchers say.

Interestingly, they found a high prognostic significance, as SATB1 was observed in early-stage breast tumours, before any spread to the lymph nodes. The researchers say this might be useful in predicting the likelihood of disease progression in early-stage cancers.