Mutant K-Ras increases GSK-3β gene expression via an ETS-p300 transcriptional complex in pancreatic cancer

Glycogen synthase kinase-3 beta (GSK-3 beta) is overexpressed in a number of human malignancies and has been shown to contribute to tumor cell proliferation and survival. Although regulation of GSK-3 beta activity has been extensively studied, the mechanisms governing GSK-3 beta gene expression are still unknown. Using pancreatic cancer as a model, we find that constitutively active Ras signaling increases GSK-3 beta gene expression via the canonical mitogen-activated protein kinase signaling pathway. Analysis of the mechanism revealed that K-Ras regulates the expression of this kinase through two highly conserved E-twenty six (ETS) binding elements within the proximal region. Furthermore, we demonstrate that mutant K-Ras enhances ETS2 loading onto the promoter, and ETS requires its transcriptional activity to increase GSK-3 beta gene transcription in pancreatic cancer cells. Lastly, we show that ETS2 cooperates with p300 histone acetyltransferase to remodel chromatin and promote GSK-3 beta expression. Taken together, these results provide a general mechanism for increased expression of GSK-3 beta in pancreatic cancer and perhaps other cancers, where Ras signaling is deregulated. Oncogene (2011) 30, 3705-3715; doi:10.1038/onc.2011.90; published online 28 March 2011