The higher-order organization of chromatin plays an important role in regulating gene expression. Special AT-rich binding protein 1 (SATB1), which has a cage-like nuclear distribution, has a role in chromatin folding. SATB1 is a novel global gene regulator, regulating expression of hundreds of genes by tethering its target genes onto the SATB1 """"""""platform"""""""" by binding to specialized DNA sequences. SATB1 recruits chromatin remodeling/modifying enzymes and regulatory transcription factors to its target gene loci. Our lab has recently found SATB1 to be expressed by aggressive but not by non-aggressive human breast cancer cells. Once SATB1 is expressed in breast cancer, it reprograms expression of a large body of genes, for instance by upregulating metastasis-promoting genes and downregulating tumor suppressor genes, to promote tumor growth and metastasis. Knockdown of SATB1 from aggressive breast cancer inhibited tumor growth and metastasis. And SATB1 has proven to be a prognostic factor independent of the lymph node status in breast cancer patients. These results highlight a crucial role for genome organization in regulating breast cancer progression. Our lab demonstrated that global gene regulation by SATB1 in breast cancer involves epigenetic changes at the level of histone modification. In this project, I will explore how SATB1 promotes breast cancer metastasis, by testing a hypothesis that SATB1 affects DNA methylation as well. Preliminary data in our lab have also revealed that SATB1 plays an important role in DNA repair in T cells. I will test a hypothesis that SATB1 expression promotes DNA repair in breast cancer cells and thus promotes acquisition of drug resistance for these cells. I will test whether downregulation of SATB1 from drug resistant breast cancer cells reverses tumorigenesis. This project examines the epigenetic mechanisms underlying breast cancer metastasis, focusing on DNA methylation. These studies also address SATB1's new role in acquisition of drug resistance of breast cancer cells. The results from these studies may reveal an important basic mechanism, which could be used to develop breast cancer therapies for the treatment of aggressive, drug-resistant breast cancer in the future.
|Kohwi-Shigematsu, Terumi; Poterlowicz, Krzysztof; Ordinario, Ellen et al. (2013) Genome organizing function of SATB1 in tumor progression. Semin Cancer Biol 23:72-9|
|Ordinario, Ellen; Han, Hye-Jung; Furuta, Saori et al. (2012) ATM suppresses SATB1-induced malignant progression in breast epithelial cells. PLoS One 7:e51786|