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

TL;DR

This study shows how abnormal NRF2 activity in lung cancer cells leads to aggressive tumor growth by changing gene regulation.

Contribution

The study reveals a new mechanism where NRF2 and CEBPB work together to create enhancers that promote tumor-initiating activity in lung cancer.

Findings

Persistent NRF2 activation creates enhancers at specific gene loci in non-small cell lung cancers.

The CEBPB protein is essential for forming these enhancers, particularly the NOTCH3 enhancer.

The NRF2-CEBPB interaction promotes tumor-initiating activity and cancer malignancy.

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.

Aberrant activation of NRF2 in cancer cells contributes to tumorigenicity and therapeutic resistance. Here, the authors show that NRF2 cooperates with CEBPB and remodels enhancers to confer tumor-initiating activity on NRF2- activated non-small cell lung cancers.

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