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-��B in triple negative breast cancer (TNBC). We profile EZH2 and NF-��B factor co-localization and positive gene regulation genome-wide, and define a subset of NF-��B 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-��B-dependent genes, and supports downstream migration and stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-��B 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-��B-dependent regulatory mechanisms.
