Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells

Abstract

The STAT proteins (signal transducers and activators of transcription) are transcription factors mediating cytokine/growth factor signaling, which play important role in controlling cell cycle progression and apoptosis. In many cancer cell lines and tumors (including gliomas) the STAT proteins (in particular Stats 1, 3, and 5) are persistently activated. In this study, we employed DNA decoys, siRNAs, and protein overexpression, to elucidate the role of Stat1 and Stat3 in regulation of expression of endogenous Stat3-target genes (Bcl2l1, Myc, Ccnd1) and a Stat-driven reporter plasmid, in rat C6 glioma cells. The results obtained with the decoys and siRNA suggest that in proliferating C6 cells, Stat1 supports the basal expression of Bcl2l1, while the decoy and chromatin immunoprecipitation results suggest it also plays a similar role for Myc. In the Stat-driven reporter system, overexpression of Stat1 stimulated, while overexpression of Stat3 inhibited the reporter gene expression. The level of Stat1 phosphorylation observed under basal conditions in proliferating glioma C6 cells is very low. Therefore, we speculate that it is the activity of the unphosphorylated Stat1 that is inhibited by Stat1 decoy or Stat1 siRNA. Taken together, our results demonstrate that it is Stat1 not Stat3 that maintains the expression of Bcl2l1 and possibly Myc in proliferating glioma C6 cells. An established paradigm is that Stat3 exerts a pro-survival and potentially oncogenic effects, while Stat1 is mainly associated with the immune response. Our results add to a number of reports that challenge this paradigm.