Yi Cheng, Li Guangyue, Wang Wenmeng, Sun Yixuan, Zhang Yueling, Zhong Chen, Stovall Daniel B, Li Dangdang, Shi Jinming, Sui Guangchao
Key Laboratory of Saline-Alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin 150040, China.
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.
Cancers (Basel). 2021 May 16;13(10):2402. doi: 10.3390/cancers13102402.
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.
zeste同源物2增强子（EZH2）是一种甲基转移酶，可介导组蛋白H3赖氨酸27三甲基化（即H3K27me3）并抑制基因表达。在实体瘤中，EZH2促进肿瘤发生，被认为是一个治疗靶点。作为一种转录因子，阴阳1（YY1）通过其癌蛋白结合（OPB）结构域招募EZH2以建立基因抑制。在本研究中，我们将EZH2上的YY1蛋白结合（YPB）结构域定位到一个27个氨基酸的区域。YPB和OPB结构域合成肽均可破坏YY1-EZH2相互作用，显著降低乳腺癌细胞活力，并在异种移植小鼠模型中有效抑制肿瘤生长。我们使用抗H3K27me3抗体，通过染色质免疫沉淀DNA测序（ChIP-seq）分析了用YPB、OPB和对照肽处理的MDA-MB-231细胞。与对照相比，YPB和OPB处理分别改变了465个和1137个基因上的H3K27me3。在这些基因中，两种肽之间有145个重叠。其中，PTEN假基因PTENP1在用YPB或OPB肽处理时显示H3K27me3信号降低。一致地，这两种肽增强了PTENP1和PTEN的表达，同时降低了AKT激活。进一步的研究验证了PTENP1对YPB和OPB肽抗癌活性的贡献。
