Yu Huimei, Jiang Yuanyuan, Liu Lanxin, Shan Wenqi, Chu Xiaofang, Yang Zhe, Yang Zeng-Quan
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
College of Basic Medicine, Jilin University, Changchun, China.
Oncotarget. 2017 Feb 21;8(8):13099-13115. doi: 10.18632/oncotarget.14402.
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finger, MYND-type containing 8), ASXL1 (additional sex combs like 1) and CHD3 (chromodomain helicase DNA binding protein 3). Copy number increase and overexpression of ZMYND8 were more prevalent in Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. ZMYND8 was also involved in a positive feedback circuit of the estrogen receptor (ER) pathway, and the expression of ZMYND8 was repressed by the bromodomain and extra terminal (BET) inhibitor in breast cancer. Our findings suggest a promising avenue for future research-to focus on a subset of PHFs to better understand the molecular mechanisms and to identify therapeutic targets in breast cancer.
一系列调控染色质修饰、基因表达、基因组稳定性和DNA修复的表观遗传效应因子包含结构保守的结构域，称为植物同源结构域（PHD）指。由于基因组扩增、突变、缺失和易位导致的几种含PHD指蛋白（PHF）的改变已直接与各种类型的癌症相关联。然而，关于PHF在乳腺癌中的基因组格局和临床意义知之甚少。因此，我们使用TCGA和METABRIC数据集对乳腺癌中的98个PHF基因进行了大规模的基因组和转录组分析，并将复发性改变与患者的临床病理特征和生存情况相关联。乳腺癌的不同亚型对每个PHF具有不同的拷贝数和表达模式。我们鉴定出一组复发性改变且发生率高的PHF基因，包括PYGO2（pygopus家族PHD指2）、ZMYND8（含锌指、MYND型8）、ASXL1（类额外性梳1）和CHD3（染色质结构域解旋酶DNA结合蛋白3）。ZMYND8的拷贝数增加和过表达在Luminal B亚型中更为普遍，并且与乳腺癌患者的较短生存期显著相关。ZMYND8还参与雌激素受体（ER）途径的正反馈回路，并且在乳腺癌中ZMYND8的表达受到溴结构域和额外末端（BET）抑制剂的抑制。我们的研究结果为未来的研究提供了一个有前景的途径——关注一组PHF以更好地理解分子机制并确定乳腺癌的治疗靶点。
