MS275 up-regulates Fas expression through down-regulation
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Abstract
Despite aggressive chemotherapy treatments, prognosis for patients with lung metastases from osteosarcoma (OS) remains poor. It is thus important to pursue new therapeutic approaches. The ability of osteosarcoma cells to form lung metastases has been inversely correlated to cell surface Fas expression. Down-regulation of Fas allows OS cells to avoid FasL-mediated apoptosis within the FasL positive lung microenvironment. The histone deacetylase inhibitor, MS275, has been shown to up-regulate Fas expression in Fas negative LM7 OS cells and induce regression of established OS lung metastases. But the mechanism through which MS275 exerts its effect is unknown.
Recently, studies have shown that overexpression of miR-20a, which is part of the miR-17-92 cluster, results in the down-regulation of Fas expression in SAOS-2 cells and a decreased sensitivity to FasL. Thus, a potential mechanism through which MS275 up-regulates Fas expression is through the regulation of miR-17-92 and miR-20a. In the current study, LM7 cells were treated with MS275 and its effects on miRNA expression were studied. To address the underlying mechanism of MS275, we characterized the effect of MS275 on miRNA gene transcription and degradation. MS275 suppressed miR-17-92 and miR-20 levels in a time dependent manner. Although MS275 decreased miRNA expression, it enhanced the promoter activity for miR-17-92 as measured by luciferase assay, suggesting that the decrease in miRNA following MS275 treatment is mediated through a post-transcriptional mechanism. Experiments using actinomycin D, a DNA transcription inhibitor, and cycloheximide, a protein translation inhibitor, demonstrated that MS275 did not function by enhancing post-transcriptional degradation. This data suggests that down-regulation of miR-20a by MS275 may occur through other factors that remain to be described.
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This presentation is supported by the National Cancer Institute through the U54 CA096297/CA096300: UPR/MDACC Partnership for Excellence in Cancer Research Training Program.
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