Isoliquiritigenin attenuates MiR-21 expression via induction of PIAS3 in breast cancer cells

We have previously documented that isoliquiritigenin (ISL), a dietary compound extracted from licorice, could exert anti-breast cancer effects via inhibition of miR-21, however, the intrinsic mechanisms remain obscure. Herein, we discovered that ISL down-regulated the primary miR-21 (pri-miR-21) and mature miR-21 expression in a dose-dependent manner, indicating transcriptional silencing of miR-21. The transcriptional factor signaling transducer and activator of transcription 3 (STAT3) could transcriptionally activate miR-21 expression. Our luciferase reporter and ChIP assay data demonstrated that ISL reduced the activity of STAT3 signaling by approximately 70% and the enrichment of activated STAT3 within miR-21 promoter in breast cancer cells. Next we found that ISL induced protein inhibition of activated STAT3 (PIAS3) a specific inhibitor of activated STAT3. Additionally, abrogation of PIAS3 via transfection of specific siRNA abolished the inhibitory effect of ISL on the activity of STAT3 signaling pathway and miR-21 expression. Taken together, our study documented for the first time that induction of PIAS3 mediated STAT3 signaling inhibition was responsible for the repression of miR-21 by ISL.