Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers

SummaryBoth EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional crosstalk in breast cancer is unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in ER-positive luminal-like breast cancer cells and represses NF-κB target gene expression by interacting with ER and directing repressive histone methylation on their promoters. Thus, EZH2 functions as a double-facet molecule in breast cancers, either as a transcriptional activator or repressor of NF-κB targets, depending on the cellular context. These findings reveal an additional mechanism by which EZH2 promotes breast cancer progression and underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (179 K)Download as PowerPoint slideHighlights► EZH2 promotes expression of NF-κB targets in basal-like breast cancer (BLBC) ► Regulation of NF-κB targets is independent of EZH2 catalytic activity in BLBC ► EZH2 physically interacts with RelA and RelB in BLBC ► EZH2 represses expression of NF-κB targets in ER-positive breast cancers