Down-regulation of the global regulator SATB1 by statins in COLO205 colon cancer cells

Abstract

Abstract. Special aT-rich sequence binding protein 1 (SaTB1) regulates the expression of more than 1,000 genes in tumor cells. SaTB1 expression has been implicated in metastasis, and its silencing results in reduced cancer progression and the reversion of metastatic cells to normal appearance. Therefore, any compound causing down-regulation of SaTB1 expression or activity may be exploited for its therapeutic potential in terms of cancer regression. earlier studies showed that the 3-hydroxy-3-methylglutaryl coenzymea (HMG-coa) reductase inhibitors (statin drugs), which are widely used to treat hypercholesterolemia, possess other pleotropic activities. These are now increasingly gaining attention for their cancer prevention abilities. However, the downstream interplay of the molecular mechanisms of such anti-cancer activities is unclear. Here, we show that SaTB1 is down-regulated by statins in a time-and dose-dependent manner in colo205 cells. This effect was statin-specific as the down-regulation of SATB1 was brought about by hydrophobic statins, such as simvastatin and fluvastatin, but not by hydrophilic pravastatin. Notably, treatment with mevalonate, an intermediate in the cholesterol and isoprenoid biosynthetic pathways, led to the inhibition of SaTB1 down-regulation and cytotoxicity mediated by statins. Treatment with the proteasome inhibitors lactacystine and MG-132 inhibited the statin-mediated down-regulation of SaTB1, suggesting that regulation occurs at the post-translational level. Thus, our results demonstrate a novel molecular mechanism for the anti-cancer activity of statin drugs in colon cancer cells, without invoking significant cytotoxicity.

The Role of SATB1 in Tumour Progression and Metastasis

“…These results may suggest that it could be a promising target for novel anticancer drugs. Baicalein and hydrophobic statins were shown to successfully down-regulate the level of SATB1 in breast and colorectal cancer cells respectively, causing a significant decrease in cells’ proliferation and invasion abilities [60,61,127]. The co-delivery of SATB1 shRNA and doxorubicin by using immunoliposomes was shown to have an antitumor effect on gastric cancer cells [111].…”

Divergent expression patterns of SATB1 mRNA and SATB1 protein in colorectal cancer and normal tissues

“…Also, miR-7 and miR-155 were shown to be involved in the posttranscriptional regulation of SATB1 gene expression in breast cancer cells [ 24 ]. SATB1 expression in COLO205 colon cancer cells was downregulated by statins via posttranslational modifications of SATB1 protein which led to targeting it for proteolytic degradation [ 25 ]. Dysregulation of hypothetical SATB1 expression-controlling mechanism in colorectal tissue could lead to an aberrant SATB1 expression and result in global, tumor-promoting changes in affected cells.…”

Silencing SATB1 Inhibits the Malignant Phenotype and Increases Sensitivity of Human Osteosarcoma U2OS Cells to Arsenic Trioxide

“…These results indicate that ATO plus SATB1 silencing may be a promising therapeutic approach for treating osteosarcomas in which SATB1 is over-expressed, even though more studies are needed to increase its efficiency and decrease adverse reactions. It has also been reported that SATB1 could be down-regulated by the 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors (statin drugs) 29 which are widely used to treat hypercholesterolemia. These results provide a practical way to down regulate SATB1, without invoking significant cytotoxicity.…”