This R03 proposal seeks to investigate molecular mechanisms during reflux-induced neoplasia in Barrett's esophagus to generate preliminary data for a future R01 application. AKT1 phosphorylation by upstream oncogenic kinases promotes esophageal adenocarcinoma, one of most rapidly increasing lethal malignancies, in reflux injury induced Barrett's metaplasia. 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 critical 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 IL-1? induces Histone Acetyl Transferase (HAT) p300 that acetylates histone residues in promoter chromatin. Moreover, both IL-1? and its downstream target STAT3 that is known to recruit p300 up-regulate AKT1 expression. The mechanistic details of this pathway, in context of chromatin remodeling of AKT1 during neoplastic transformation in Barrett's, remain to be characterized. Based on these observations, our CENTRAL HYPOTHESIS is that pro- inflammatory IL-1? STAT3 signaling induces AKT1 expression via chromatin-mediated mechanisms to promote neoplastic progression in Barrett's esophagus and pharmacological inhibition of this pathway will prevent esophageal adenocarcinoma. We have three specific aims.
Our first aim will test that IL-1? increases STAT3 binding to AKT1 promoter to increase AKT1 promoter activity and expression. In the second aim we will test whether IL-1? mediated up-regulation of transcriptional co-activator p300 and activation of transcription factor STAT3 cooperate to place activating acetylation marks on AKT1 chromatin, induce AKT1 expression and promote cell growth. Finally, in the third translational aim we will test that disrupting STAT3 activation and p300 function by natural compound Garcinol abrogates AKT1 chromatin acetylation and reduces the risk of IL-1? induced esophageal adenocarcinoma in-vivo. This mechanistic, hypothesis-driven approach will elicit novel pathobiological information, identify disease prevention strategies, and provide key preliminary data for R01 application.
Heartburn is a common health problem. 20% of Americans suffer from heartburn. 6% of them can develop Barrett's Esophagus. Patients with Barrett's Esophagus are at risk of cancer of the esophagus. This is one of the most rapidly increasing lethal cancers in the United States. Our research will examine the pathways that lead to this. The goal will be to target these pathways using safe agents to prevent this cancer.