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

Abstract

Both 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.

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

“…1B); this result is consistent with the antagonistic relationship between HIF1-α and HIF2-α reported previously in breast cancer (34). These observations indicate that the differential regulation of Ezh2 and PRC2 function in different subtypes of breast cancer might be associated with HIF1-α and that the up-regulation of Ezh2 in TNBC may implicate a PRC2-independent function, supporting previously reported non-PRC2 activity of Ezh2 in TNBC (8,13). …”

“…Thus, the oncogenic function of Ezh2 in TNBC is not well coupled with the H3K27me3 level; instead, it might be more connected to its nonepigenetic silencing effect. Indeed, discrete functions of Ezh2, independent of PRC2, have been found to regulate NF-κB (8) and Notch pathways positively in TNBC (13). Furthermore, the inverse correlation between EZH2 and H3K27me3 levels seen in TNBC seems to indicate an impaired PRC2 activity in TNBC.…”

“…In multiple malignancies including breast cancer, the up-regulation of Ezh2 is positively correlated with tumor grade, metastasis propensity, and poor survival rate (7). The oncogenic function of Ezh2 has been linked to both PRC2-dependent and PRC2-independent activities (8)(9)(10)(11)(12)(13). Paradoxically, a context-dependent tumor-suppressive function of Ezh2 or PRC2 also has been reported in several malignancies (14)(15)(16)(17)(18).…”

Molecular switch of EZH2 in hypoxia

“…2 Of the alteration in the protein partners of Ezh2 identified in this study, the presence of a canonical PRC2 is not completely abrogated; rather they exist concurrently in the context of TNBC model.…”

Au cœur d’une complexité biologique

“…B. Le nouveau modèle hiérarchique proposé par Blackledge et al [19] [27]. EZH2 fonctionne également comme un activateur transcriptionnel, dans les cancers de la prostate résistants à la castration [28], ou dans les lymphomes de cellules NKT (natural killer T) [29].…”