Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 
3 (PIAS3) is a molecule that regulates STAT3 and has antiproliferative 
properties. Glioblastoma and squamous cell lung cancer lack PIAS3 expression. To 
test the hypothesis that PIAS3 transcriptional effects are STAT3-independent, we 
developed models for STAT3 knockdown and PIAS3 over-expression. PIAS3 expression 
results in a distinct transcriptional profile that does not occur with STAT3 
knockdown. We identify novel transcription factor binding partners for PIAS3 
including ETS, EGR1, NR1I2, and GATA1. PIAS3 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 PIAS3 effects EGR1 regulated 
pathways.