An EZH2-NF-κB regulatory axis drives expression of pro-oncogenic gene signatures in triple negative breast cancer

Gabrielle J Dardis; Jun Wang; Jeremy M Simon; Gang Greg Wang; Albert S Baldwin

doi:10.1016/j.isci.2023.107115

An EZH2-NF-κB regulatory axis drives expression of pro-oncogenic gene signatures in triple negative breast cancer

iScience. 2023 Jun 14;26(7):107115. doi: 10.1016/j.isci.2023.107115. eCollection 2023 Jul 21.

Authors

Gabrielle J Dardis^{1

2}, Jun Wang^{1

2}, Jeremy M Simon^{1

3

4}, Gang Greg Wang^{1

2}, Albert S Baldwin¹

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
³ Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
⁴ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

The histone methyltransferase EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting paradoxical gene expression through interactions with transcription factors, including NF-κB in triple negative breast cancer (TNBC). We profile EZH2 and NF-κB factor co-localization and positive gene regulation genome-wide, and define a subset of NF-κB targets and genes associated with oncogenic functions in TNBC that is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified transactivation domain (TAD) which mediates EZH2 recruitment to, and activation of certain NF-κB-dependent genes, and supports downstream migration and stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-κB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-κB-dependent regulatory mechanisms.

Keywords: Biochemistry; Biological sciences; Cancer; Cancer systems biology; Natural sciences; Systems biology.