Deciphering the landscape of GATA-mediated transcriptional regulation in gastric cancer
Gastric cancer (GC) is an asymptomatic malignancy in early stages, with a limited and cost-ineffective diagnostic toolbox that globally contributes to severe mortality rates on an annual basis. Ectopic expression of the lineage survival transcription factors (LS-TFs) GATA 4 and 6 promotes stomach oncogenesis, at the stage of premalignant gastric lesions. However, LS-TFs play important physiological roles that hinder their direct therapeutic targeting, therefore their downstream target genes are of particular interest for developing cancer-specific molecular biomarkers or therapeutic agents. In this work we couple inducible knock-down systems with chromatin immunoprecipitation and RNA-seq to thoroughly detect and further characterize direct targets of GATA-mediated transcriptional regulation in gastric cancer cells. Our experimental and computational strategy provides evidence that these transcription factors regulate the expression of several coding and non-coding RNAs that in turn mediate for their cancer-promoting phenotypes. Finally, the prognostic and diagnostic potential of selected target transcripts is evaluated in patient biopsies, emphasizing on gastrointestinal tumors. Overall design: Comparative gene expression profiling analysis of RNA-seq data for AGS cells following inducible GATA4 and 6 knock-down