Abstract
STAT6 transcription factor has become a potential molecule for therapeutic intervention because it regulates broad range of cellular processes in a large variety of cell types. Although some target genes and interacting partners of STAT6 have been identified, its exact mechanism of action needs to be elucidated. In this study, we sought to further characterize the molecular interactions, networks, and functions of STAT6 by profiling the mRNA expression of STAT6 silenced human lung cells (NCI-H460) using microarrays. Our analysis revealed 273 differentially expressed genes after STAT6 silencing. Analysis of the gene expression data with Ingenuity Pathway Analysis (IPA) software revealed Gene expression, Cell death, Lipid metabolism as the functions associated with highest rated network. Cholesterol biosynthesis was among the most enriched pathways in IPA as well as in PANTHER analysis. These results have been validated by real-time PCR and cholesterol assay using scrambled siRNA as a negative control. Similar findings were also observed with human type II pulmonary alveolar epithelial cells, A549. In the present study we have, for the first time, shown the inverse relationship of STAT6 with the cholesterol biosynthesis in lung cancer cells. The present findings are potentially significant to advance the understanding and design of therapeutics for the pathological conditions where both STAT6 and cholesterol biosynthesis are implicated viz. asthma, atherosclerosis etc.
Highlights
Signal transducer and activator of transcription-6 (STAT6) is one of the seven members of the family of transcription factors that participate in the regulation of gene expression when cells encounter various extracellular polypeptides like cytokines, hormones and growth factors and regulate a broad range of cellular processes including proliferation, differentiation and apoptosis [1,2,3,4]
Shum et al in 2006 provided a link between allergic inflammation and fatty acid metabolism where they have shown that an IL-4/STAT6 regulated gene aP2, which plays an important role in lipid metabolism, is required in Th2 mediated allergic airway inflammation [16] and recently STAT6 has been found to play a role in regulating lipid homeostasis in liver as increased lipid deposition was observed in STAT6 knockout mice [17]
To gain an understanding of the biological alterations we investigated the transcriptome before and after STAT6 silencing in NCI-H460 cells using illumina microarray
Summary
STAT6 is one of the seven members of the family of transcription factors that participate in the regulation of gene expression when cells encounter various extracellular polypeptides like cytokines, hormones and growth factors and regulate a broad range of cellular processes including proliferation, differentiation and apoptosis [1,2,3,4]. Just like the other members of the STAT family, STAT6 plays a dual role of signal transducer and activator of transcription by either directly regulating gene expression or by interacting with a wide variety of other transcription factors [7]. STAT6 plays a key role in T cell hepatitis via enhancing expression of eotaxins in hepatocytes and endothelial cells, and induces IL-5 expression, infiltration of eosinophils and neutrophils into the liver and leading to hepatitis [12]. Das et al in 2007 found that STAT6 is a constitutively expressed survival factor in human prostate cancer [18] This effect of STAT6 was further strengthened in a study by Cui et al in 2007, where they have shown that unphosphorylated STAT6 transcriptionally up regulates COX-2 expression and protects against apoptosis in NSCLC (non-small cell lung cancer) cells [19]
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