STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer
Open accessAbstract
BACKGROUND: 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. RESULTS: We 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. CONCLUSIONS: These 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.
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This provides a strong link between pro-inflammatory immune factors, body growth through activation of the mTOR pathway and uncontrolled proliferation typical of cancer-related disease.
“This provides a strong link between pro-inflammatory immune factors, body growth through activation of the mTOR pathway and uncontrolled proliferation typical of cancer-related disease [150, 151–153].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [152]
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- Authors
- Fleming, J. D., Giresi, P. G., Lindahl-Allen, M., Krall, E. B., Lieb, J. D., & Struhl, K.
- Affiliations
- Harvard University (US)
- University of Chicago (US)
- Corresponding author
- Fleming, Joseph D
- Giresi, Paul G
- Lindahl-Allen, Marianne
- Lieb, Jason D
- Struhl, Kevin
- Venue
- Epigenetics & Chromatin
- Published
- 2015-02-14
- Volume
- 8
- Issue
- 1
- Pages
- 7-7
- ISSN
- 1756-8935 (ISSN-L)
- PMC
- PMC4362815
- OpenAlex
- W2168351521
- Cited by
- 39
- References
- 35
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 6 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 1
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Epigenetics & Chromatin (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Hope Funds for Cancer Research (HFCR-11-03-03)
- National Institutes of Health
- National Cancer Institute (R01CA107486)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- STAT3, FOS, AP-1, nucleosome-depleted regions, open chromatin, epigenetic switch, NF-κB, NFKB1, interleukin-6, transcription factor binding sites, FAIRE, positive feedback loop
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