An oncogenic KRAS transcription program activates the RHOGEF ARHGEF2 to mediate transformed phenotypes in pancreatic cancer.

摘要: // Oliver A. Kent 1 , Maria-Jose Sandi Helen E. Burston Kevin R. Brown 2 Robert Rottapel 1, 3, 4, 5, 6 Princess Margaret Cancer Centre, University Health Network, Toronto Medical Discovery Tower, of Toronto, Canada Donnelly Centre and Banting Best Department Research, 3 Medicine, St. Michael’s Hospital, 4 Biophysics, 5 Immunology, Division Rheumatology, Correspondence to: Kent, email: kent.uhn@gmail.com Rottapel, rottapel@gmail.com Keywords: KRAS, ARHGEF2, GEFH1, transcription, pancreatic Received: July 29, 2016     Accepted: October 13, Published: November 7, 2016 ABSTRACT Activating mutations KRAS are nearly ubiquitous in adenocarcinomas occurring greater than 90% cases. Cellular transformation by oncogenic RAS requires the RHO guanine exchange factor ARHGEF2 (also known as GEF-H1) for tumor growth survival. Here, we find activates through a minimal responsive promoter. We have determined endogenous promoter is positively regulated transcription factors ELK1, ETS1, SP1 SP3 negatively element binding protein (RREB1). that panel -regulating modulates transformed phenotypes including cellular viability, anchorage-independent invasion-migration cancer cells. RREB1 knockdown amplitude duration RHOA via increased expression. By relieving negative regulation on promoter, ETS1 essential normal expression contribute to migratory behavior Furthermore, enforced rescues loss driven defective restored activation RHOA. Collectively, our results identify program required provide mechanistic insight into highly metastatic cancer.