title: 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.
authors: Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology, and Research), Biopolis, Singapore 138672, Republic of Singapore.
authors: Shuet Theng
authors: ST
authors: Lee
authors: Zhimei
authors: Z
authors: Li
authors: Zhenlong
authors: Z
authors: Wu
authors: Meiyee
authors: M
authors: Aau
authors: Peiyong
authors: P
authors: Guan
authors: R K Murthy
authors: RK
authors: Karuturi
authors: Yih Cherng
authors: YC
authors: Liou
authors: Qiang
authors: Q
authors: Yu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005809:Genes, Regulator; D006801:Humans; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2