Identification of STAT3-independent regulatory effects for protein inhibitor of activated STAT3 by binding to novel transcription factors

Abstract

Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3 (PIAS 3) is a molecule that regulates STAT3 and has antiproliferative properties. Glioblastoma and squamous cell lung cancer lack PIAS 3 expression. To test the hypothesis that PIAS 3 transcriptional effects are STAT3-independent, we developed models for STAT3 knockdown and PIAS 3 overexpression. PIAS 3 expression results in a distinct transcriptional profile that does not occur with STAT3 knockdown. We identify novel transcription factor binding partners for PIAS 3 including ETS, EGR1, NR1I2 and GATA1. PIAS 3 binds to these factors and regulates their transcriptional effects resulting in alterations in canonical pathways including Wnt/β-catenin signaling and functions such as cell death and proliferation. A model is proposed by which PIAS 3 effects EGR1 regulated pathways. © 2011 Landes Bioscience.