Principal Investigator: Navtej S. Buttar
Institution: Mayo Clinic
Year Awarded: 2013
Project Title: Epigenetic Regulation of AKT-1 Expression by IL 1 β-STAT3: Linking Inflammation to Neoplasia in Barrett’s Esophagus
This proposal seeks to investigate molecular mechanisms during reflux-induced neoplasia inBarrett’s. AKT1 phosphorylation by upstream oncogenic kinases promotes neoplasia in Barrett's. We made the novel observation that there is a marked up-regulation of AKT1 expression during neoplastic transformation in patients with Barrett’s and that this aberrant expression increases Barrett’s epithelial cell growth both in-vitro and in-vivo. Regulation of AKT1 expression is an underrepresented research area and a key knowledge gap.
Our preliminary data demonstrate that although DNA methylation status of AKT1 does not change during neoplastic progression in Barrett’s, native AKT1 promoter chromatin shows a marked increase in acetylation of histone residues that are associated with gene activation. We uncovered that pro-inflammatory oncogenic IL1β-STAT3 up-regulate AKT1 expression. The mechanistic details of this pathway, in context of chromatin remodelling of AKT1 during neoplastic transformation in Barrett’s, remain to be characterized.
Hypothesis: pro-inflammatory IL1β-STAT3 signaling induces AKT1 expression and cell growth via mechanisms involving the acetylation of histones in AKT1 chromatin.
We have three specific aims. Our first aim will test that the activation marks on AKT1 chromatin are STAT3 dependent and IL-1β mediated up-regulation of p300 facilitates this. In the second aim we will test that IL-1β increase STAT3 binding to AKT1 promoter and pSTAT3 is required for IL-1β mediated increase in AKT1 expression. Finally, in the third aim we will test that IL-1β requires STAT3 to up regulate AKT1 expression in-vivo and change cell growth. This mechanistic, hypothesis-driven approach will elicit novel pathobiological information and identify diseaseprevention strategies.