Overexpression and involvement of special AT‐rich sequence binding protein 1 in multidrug resistance in human breast carcinoma cells

Abstract

Special AT-rich sequence binding protein (SATB) 1 has been proposed to act as a determinant for the acquisition of metastatic activity by controlling expression of a specific set of genes that promote metastatic activity. Here we found that SATB1 expression is upregulated in multidrug-resistant breast cancer cells that exhibit higher invasive potential than the parental cells. Apart from accelerating metastasis and inducing epithelial-mesenchymal transition, SATB1 was demonstrated to confer resistance to both P-glycoprotein-related and P-glycoprotein-non-related drugs on MCF7 cells, which was accompanied by decreasing accumulation of adriamycin in SATB1-overexpressing transfectants. SATB1 depletion could partially reverse the multidrug resistance (MDR) phenotype of MCF7 ⁄ ADR in vitro and in vivo. The SATB1-induced P-glycoprotein-mediated MDR could be reversed by treatment with anti-Pglycoprotein mAb. Moreover, SATB1 plays an important role in anti-apoptotic activity in MCF7 ⁄ ADR cells in response to adriamycin treatment, which suggests another mechanism contributing to SATB1-related MDR of breast cancers. These data provide new insights into the mode by which breast tumors acquire the MDR phenotype and also imply a role for SATB1 in this process. (Cancer Sci 2010; 101: 80-86) S pecial AT-rich sequence binding protein (SATB) 1, the global chromatin organizer and transcription factor, has emerged as a key factor in regulating gene expression during the differentiation and activation of T cells, making it a key player in the immune system.(1) Previous studies have unraveled the role of SATB1 in the organization of the chromatin ''loopscape'' and its dynamic nature in response to physiological stimuli. At the genome-wide level, SATB1 seems to play a role in the organization of the transcriptionally poised chromatin. (2,3) SATB1 organizes the MHC class I locus into distinct chromatin loops by tethering matrix association regions to the nuclear matrix at fixed distances.(4-6) Silencing of SATB1 mimics the effects of interferon (IFN)-c treatment on the chromatin loop architecture of the MHC class I locus and alters the expression of genes within the locus. Besides the immune system, SATB1 is also expressed in many cancer cells, such as colorectal cancer cells,lymphoma cells, (8) and breast cancer cells. (9) SATB1 has now revealed a darker side. Rygiel et al. found that SATB1 expression in colorectal cancer seems to be associated with an aggressive phenotype.(7) SATB1 correlates with high expression of tumor necrosis factor (TNF)-a, which mediates the inflammatory processes in tumor invasion, angiogenesis, and metastasis. On the other hand, SATB1 influences the expression of anti-inflammatory interleukin (IL)-4 and IL-10, which in turn are known to lead to escape from cancer immune surveillance. In addition, SATB1 is also an essential contributing factor in the most aggressive forms of breast cancer.(9) By introducing SATB1 into otherwise non-metastatic breast cancer cells, invasive tumors can be induced in mice; ...

Special AT-rich sequence binding protein 1 regulates the multidrug resistance and invasion of human gastric cancer cells

“…Notably, VCR-induced apoptosis was largely eliminated by SATB1 overexpression in SGC7901 cells. These results are consistent with previous studies which revealed that SATB1 inhibited apoptosis in Sézary and breast cancer cells (14,23), suggesting that the SATB1-mediated inhibition of apoptosis may contribute to MDR in gastric cancer.…”

“…Furthermore, previous studies have suggested that SATB1 is a master regulator of breast cancer growth and metastasis (1,13). Notably, Li et al recently reported that SATB1 was able to upregulate certain genes associated with MDR and suppress drug-induced apoptosis in breast cancer, indicating the role of SATB1 in MDR (14).…”

Expression and significance of SATB1 in the development of breast cancer

“…Some of the multidrug-resistant phenotype was reversed when the level of SATB1 was reduced. Previous studies suggested that SATB1 mediates the resistance of tumor cells by inhibiting tumor cell apoptosis (Li et al, 2010). Another study found that chemotherapy can reduce the level of microRNA-448.…”

SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21

“…been associated with varied malignancies [14][15][16][17] ; however, its status in CTCLs other than Sézary syndrome is unknown.…”