Abstract
BackgroundTransient induction of the Src oncoprotein in a non-transformed breast cell line can initiate an epigenetic switch to a cancer cell via a positive feedback loop that involves activation of the signal transducer and activator of transcription 3 protein (STAT3) and NF-κB transcription factors.ResultsWe show that during the transformation process, nucleosome-depleted regions (defined by formaldehyde-assisted isolation of regulatory elements (FAIRE)) are largely unchanged and that both before and during transformation, STAT3 binds almost exclusively to previously open chromatin regions. Roughly, a third of the transformation-inducible genes require STAT3 for the induction. STAT3 and NF-κB appear to drive the regulation of different gene sets during the transformation process. Interestingly, STAT3 directly regulates the expression of NFKB1, which encodes a subunit of NF-κB, and IL6, a cytokine that stimulates STAT3 activity. Lastly, many STAT3 binding sites are also bound by FOS and the expression of several AP-1 factors is altered during transformation in a STAT3-dependent manner, suggesting that STAT3 may cooperate with AP-1 proteins.ConclusionsThese observations uncover additional complexities to the inflammatory feedback loop that are likely to contribute to the epigenetic switch. In addition, gene expression changes during transformation, whether driven by pre-existing or induced transcription factors, occur largely through pre-existing nucleosome-depleted regions.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-8935-8-7) contains supplementary material, which is available to authorized users.
Highlights
Transient induction of the Src oncoprotein in a non-transformed breast cell line can initiate an epigenetic switch to a cancer cell via a positive feedback loop that involves activation of the signal transducer and activator of transcription 3 protein (STAT3) and NF-κB transcription factors
Accessible chromatin regions are largely unchanged during cellular transformation Genome-wide identification of nucleosome-depleted regions by formaldehyde-assisted isolation of regulatory elements (FAIRE)-seq or DNase-seq reveals that human cells typically have approximately 100,000 such open chromatin regions, with many differences in the genomic location of such regions among different cell types [15,16]
GILZ and other transcription factor (TF) are indirectly inhibited by STAT3 during transformation There is a class of TFs whose expression is repressed early and/or late during transformation in a STAT3dependent manner (Figure 3C)
Summary
Transient induction of the Src oncoprotein in a non-transformed breast cell line can initiate an epigenetic switch to a cancer cell via a positive feedback loop that involves activation of the signal transducer and activator of transcription 3 protein (STAT3) and NF-κB transcription factors. Oncogenic transformation is often driven by the genetic alteration of protein kinases, which results in inappropriate activity of downstream transcription factors (TFs). These TFs cause changes in gene expression that mediate the phenotypes of a transformed cancerous cell type such as invasion, metastasis, loss of contactmediated growth inhibition, uncontrolled proliferation, and tumor formation. In the case of MCF10A, overexpression of STAT3-C altered the expression of 199 genes [9], it was unclear how many of these were due to direct STAT3 binding
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