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

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 para-doxical gene expression through interactions with transcription factors, including NF-kappa B in triple negative breast cancer (TNBC). We profile EZH2 and NF-kappa B factor co-localization and positive gene regulation genome-wide, and define a subset of NF-kappa B targets and genes associated with oncogenic functions in TNBC that is en-riched 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-kappa B-dependent genes, and supports downstream migration and stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-KB 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-kappa B-dependent reg-ulatory mechanisms.