STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer

Epigenetics & Chromatin
Joseph D FlemingKevin Struhl

Abstract

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. 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. These observations uncover additional complexities to the inflammatory feedback loop that are likely to...Continue Reading

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Citations

Feb 11, 2016·Seminars in Cell & Developmental Biology·Teresa A ZimmersAndrea Bonetto
Nov 7, 2015·Epigenetics : Official Journal of the DNA Methylation Society·Caren WeinhouseDana C Dolinoy
Sep 27, 2018·Alcoholism, Clinical and Experimental Research·Andrew H SmithJoel Gelernter
May 16, 2019·International Journal of Cancer. Journal International Du Cancer·Mahalakshmi KumaranSambasivarao Damaraju
Apr 2, 2020·Expert Review of Molecular Diagnostics·Charles Emmanuel Jebaraj WalterHatem Zayed
May 1, 2020·NPJ Breast Cancer·Hanan S ElsarrajFariba Behbod
Jun 24, 2018·Molecular Psychiatry·Eric CourchesneNathan E Lewis
Mar 27, 2019·Proceedings of the National Academy of Sciences of the United States of America·Zhe JiKevin Struhl
Nov 27, 2019·Cancers·Grégory VerdeilNathalie Auphan-Anezin
Sep 9, 2019·Life Sciences·Seyed Abbas MirzaeiFatemeh Elahian
Feb 13, 2021·NPJ Breast Cancer·Hanan S ElsarrajFariba Behbod

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Datasets Mentioned

BETA
PRJNA270300
GSE64536

Methods Mentioned

BETA
xenografts
FAIRE-seq
immunoprecipitation
ChIP-seq
ChIP
transfections

Software Mentioned

BEDTools
GREAT
HOMER
TMEV
R package ggplot2
ZINBA
FIMO
FAIRE
Bowtie
IPA

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