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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