Up-regulation of miR-146b and down-regulation of miR-200b contribute to the cytotoxic effect of histone deacetylase inhibitors on ras-transformed thyroid cells.

CONTEXT Histone deacetylase inhibitors (HDACis) are anticancer agents that inhibit tumor cell growth and/or survival. However, their mechanism of action remains largely undefined. Recently, we have demonstrated that HDACis induce apoptosis in a model of rat thyroid cells transformed by the v-ras-Ki oncogene (FRTL-5 v-ras-Ki). The stabilization of TNF-related apoptosis-inducing ligand (TRAIL) protein, due to its reduced ubiquitination and proteasome degradation, accounts for the apoptotic effect induced specifically by suberoylanilide hydroxamic acid (SAHA, Vorinostat) in the v-ras-Ki thyroid transformed cells. OBJECTIVE The aim of this work was to investigate whether SAHA may induce its cytotoxic effects also deregulating microRNA (miRNA) expression levels. DESIGN We analyzed the miRNA expression profile of the thyroid transformed cells, FRTL-5 v-ras-Ki, upon SAHA treatment. RESULTS Here we report that SAHA induces the down-regulation of 18 and the up-regulation of 11 miRNAs with a fold change higher than 2 in the transformed cells. Then, we focus on the miR-146b and miR-200b, respectively up-regulated and down-regulated by SAHA. We show that both these miRNAs target genes coding for proteins with a critical role in proteasome composition and ubiquitin degradation. CONCLUSION These results suggest a role of miRNA deregulation in TRAIL protein stabilization responsible for SAHA-induced apoptotic effect in thyroid transformed cells.

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