An integrated genomic analysis of Tudor domain-containing proteins identifies PHD finger protein 20-like 1 (PHF20L1) as a candidate oncogene in breast cancer.
An integrated genomic analysis of Tudor domain-containing proteins identifies PHD finger protein 20-like 1 (PHF20L1) as a candidate oncogene in breast cancer.
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DOI：
10.1016/j.molonc.2015.10.013
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发表时间：
2016-02
影响因子：
6.6
通讯作者：
Yang ZQ
中科院分区：
文献类型：
--
作者：
Jiang Y;Liu L;Shan W;Yang ZQ
都铎结构域蛋白(TDRD)识别并结合组蛋白和非组蛋白上的甲基赖氨酸/精氨酸残基，在调节染色质结构、转录、基因组稳定性和RNA代谢等方面发挥重要作用。在不同类型的癌症中已经观察到了几种TDRD的调节失调。然而，TDRDS在乳腺癌中的基因组图景和临床意义还没有得到全面的探索。在这里，我们对乳腺癌中的41个TDRD基因进行了综合的基因组和转录分析(TCGA和METABRIC数据集)，并确定了复发拷贝数改变、基因表达、临床病理特征和患者生存之间的关系。在基因扩增频率最高(>；10%)的7个TDRD中，植物同源结构域指蛋白20样蛋白1(PHF20L1)是TCGA乳腺癌中最常见的扩增TDRD基因(17.62%)。不同亚型乳腺癌TDRD的拷贝数和表达模式不同。值得注意的是，PHF20L1的扩增和过度表达在侵袭性基底细胞样亚型和腔性B亚型中更为普遍，并与乳腺癌患者的较短生存期显著相关。此外，PHF20L1基因敲除抑制了PHF20L1扩增的乳腺癌细胞系的细胞增殖。PHF20L1蛋白含有N-端的Tudor和C-端的植物同源域。PHF20L1在乳腺癌中的详细特征表明，Tudor结构域可能在促进癌症方面发挥关键作用。从机制上讲，PHF20L1可能通过稳定DNA甲基转移酶1(DNMT1)蛋白参与调控乳腺癌DNA甲基化。因此，我们的结果证明了PHF20L1的致癌潜力及其与乳腺癌预后不良参数的相关性。
Tudor domain–containing proteins (TDRDs), which recognize and bind to methyl-lysine/arginine residues on histones and non-histone proteins, play critical roles in regulating chromatin architecture, transcription, genomic stability, and RNA metabolism. Dysregulation of several TDRDs have been observed in various types of cancer. However, neither the genomic landscape nor clinical significance of TDRDs in breast cancer has been explored comprehensively. Here, we performed an integrated genomic and transcriptomic analysis of 41 TDRD genes in breast cancer (TCGA and METABRIC datasets) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. Among seven TDRDs that had the highest frequency (>10%) of gene amplification, the plant homeodomain finger protein 20-like 1 (PHF20L1) was the most commonly amplified (17.62%) TDRD gene in TCGA breast cancers. Different subtypes of breast cancer had different patterns of copy number and expression for each TDRD. Notably, amplification and overexpression of PHF20L1 were more prevalent in aggressive basal-like and Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. Furthermore, knockdown of PHF20L1 inhibited cell proliferation in PHF20L1-amplified breast cancer cell lines. PHF20L1 protein contains N-terminal Tudor and C-terminal plant homeodomain domains. Detailed characterization of PHF20L1 in breast cancer revealed that the Tudor domain likely plays a critical role in promoting cancer. Mechanistically, PHF20L1 might participate in regulating DNA methylation by stabilizing DNA methyltransferase 1 (DNMT1) protein in breast cancer. Thus, our results demonstrated the oncogenic potential of PHF20L1 and its association with poor prognostic parameters in breast cancer.