Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers

Nature Communications
Keito OkazakiHozumi Motohashi

Abstract

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

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Citations

Dec 31, 2020·Cancers·Keiko Taguchi, Masayuki Yamamoto
Feb 5, 2021·Cancers·Hiroki Sekine, Hozumi Motohashi
May 1, 2021·Metabolites·Ezequiel MonferrerTomás Álvaro Naranjo
Jul 3, 2021·Antioxidants·Tabitha Jenkins, Jerome Gouge
Aug 28, 2021·Cells·Miriam Sánchez-OrtegaAntonio Garrido
Sep 17, 2021·Communications Biology·Elena V KnatkoAlbena T Dinkova-Kostova

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Datasets Mentioned

BETA
GSE118842

Methods Mentioned

BETA
transfection
surgical resection
ChIP-seq
RNA-seq
immunoprecipitation
xenograft
ChIP
PCR
flow cytometry
affinity purification

Software Mentioned

deepTools
ImageJ
SAMTools
Excel
Cufflinks
JMP Pro
Bowtie2
Prism
GenometriCorr
BEDtools

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