Disruption of YY1-EZH2 Interaction Using Synthetic Peptides Inhibits Breast Cancer Development

文献类型： 外文期刊

第一作者： Yi, Cheng

作者： Yi, Cheng;Li, Guangyue;Wang, Wenmeng;Sun, Yixuan;Li, Dangdang;Shi, Jinming;Sui, Guangchao;Zhang, Yueling;Zhong, Chen;Stovall, Daniel B.

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关键词： EZH2; YY1; YPB; OPB; breast cancer; PTENP1

期刊名称：CANCERS （ 影响因子：6.639； 五年影响因子：6.999 ）

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年卷期： 2021 年 13 卷 10 期

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收录情况： SCI

摘要： Simple Summary Both Yin Yang 1 (YY1) and enhancer of zeste homolog 2 (EZH2) are oncogenes with overexpressed statuses in cancers. As a transcription factor, YY1 recruits EZH2 through its oncoprotein binding (OPB) domain to repress gene expression. In this study, we identified the interaction domain of YY1 on EZH2 protein with amino acids 493-519, named the YY1 protein binding (YPB) domain. Synthetic peptides using YPB and OPB domain sequences effectively blocked endogenous YY1-EZH2 interaction. Functionally, YPB and OPB peptides could efficiently inhibit the proliferation of breast cancer cells, promote their apoptosis, and reduce tumor growth in a xenograft mouse model. Using chromatin immunoprecipitation DNA sequencing (ChIP-seq) analysis, we discovered that YPB and OPB peptides could interfere with H3K27 trimethylation of multiple genes. Eventually, we identified that YPB and OPB peptides primarily targeted the PTENP1 gene and validated its importance in the anticancer activity of the two peptides. Enhancer of zeste homolog 2 (EZH2) is a methyltransferase to mediate lysine 27 trimethylation in histone H3 (i.e., H3K27me3) and repress gene expression. In solid tumors, EZH2 promotes oncogenesis and is considered a therapeutic target. As a transcription factor, Yin Yang 1 (YY1) recruits EZH2 through its oncoprotein binding (OPB) domain to establish gene repression. In this study, we mapped the YY1 protein binding (YPB) domain on EZH2 to a region of 27 amino acids. Both YPB and OPB domain synthetic peptides could disrupt YY1EZH2 interaction, markedly reduce breast cancer cell viability, and efficiently inhibit tumor growth in a xenograft mouse model. We analyzed MDA-MB-231 cells treated with YPB, OPB, and control peptides by chromatin immunoprecipitation DNA sequencing (ChIP-seq) using an antibody against H3K27me3. YPB and OPB treatments altered H3K27me3 on 465 and 1137 genes, respectively, compared to the control. Of these genes, 145 overlapped between the two peptides. Among them, PTENP1, the PTEN pseudogene, showed reduced H3K27me3 signal when treated by either YPB or OPB peptide. Consistently, the two peptides enhanced both PTENP1 and PTEN expression with concomitantly reduced AKT activation. Further studies validated PTENP1 ' s contribution to the anticancer activity of YPB and OPB peptides.

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