SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis.
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.
Han
Hye-Jung
HJ
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.
Russo
Jose
J
Kohwi
Yoshinori
Y
Kohwi-Shigematsu
Terumi
T
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D036961:Matrix Attachment Region Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009368:Neoplasm Transplantation; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference
D014408:Biomarkers, Tumor; D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human