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 anti-cancer agents that inhibit tumor cell growth and/or survival. However, their mechanism of action remains largely undefined. Recently, we have demonstrated that HDAC inhibitors induce apoptosis in a model of rat thyroid cells transformed by the v-ras-Ki oncogene (FRTL-5 v-ras-Ki). The stabilization of tumor necrosis factor-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 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.