Kan Guangyan, He Heng, Zhao Qi, Li Xiubo, Li Min, Yang Huasheng, Kim Jong Kyong
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510060, China.
Oncotarget. 2017 Jun 13;8(24):39497-39511. doi: 10.18632/oncotarget.17078.
UHRF1 (ubiquitin-like with PHD and RING finger domains 1) is a critical regulator for DNA methylation, and its frequent overexpression in human cancers has been associated with tumor-promoting effects. However, whether the overexpressed UHRF1 contributes to the establishment and maintenance of tumor methylomes and whether this process can affect the tumorigenesis remain unclear. In this study, we show that UHRF1 is highly expressed in retinoblastoma, and genomes of human primary retinoblastoma and cell lines have differential DNA methylation patterns compared with those of normal retina, characterized by lower global methylation and higher promoter methylation of tumor suppressors. However, our genome-wide DNA methylation study uncovers that UHRF1 down-modulation in retinoblastoma cells exerts minor effects on the existing methylation patterns at both bulk genome and individual gene loci, suggesting that retinoblastoma methylome is primarily maintained by other mechanisms. Furthermore, using two murine retinoblastoma models, we found that high UHRF1 expression does not alter global methylation levels in both premalignant neonatal retina and retinoblastoma tumors, implying that DNA hypomethylation may not be an early mechanism driving retinoblastoma tumorigenesis unlike what has been proposed for other types of cancer. These results suggest that tumor-promoting functions of UHRF1 in retinoblastoma are largely independent of its role in DNA methylation.
UHRF1（含PHD和RING指结构域的类泛素蛋白1）是DNA甲基化的关键调节因子，其在人类癌症中频繁过表达与肿瘤促进作用相关。然而，过表达的UHRF1是否有助于肿瘤甲基化组的建立和维持，以及这一过程是否会影响肿瘤发生仍不清楚。在本研究中，我们发现UHRF1在视网膜母细胞瘤中高表达，与正常视网膜相比，人类原发性视网膜母细胞瘤和细胞系的基因组具有不同的DNA甲基化模式，其特征是整体甲基化水平较低，肿瘤抑制因子的启动子甲基化水平较高。然而，我们的全基因组DNA甲基化研究发现，视网膜母细胞瘤细胞中UHRF1的下调对整体基因组和单个基因位点的现有甲基化模式影响较小，这表明视网膜母细胞瘤甲基化组主要由其他机制维持。此外，使用两种小鼠视网膜母细胞瘤模型，我们发现高UHRF1表达不会改变癌前新生视网膜和视网膜母细胞瘤肿瘤中的整体甲基化水平，这意味着与其他类型癌症所提出的情况不同，DNA低甲基化可能不是驱动视网膜母细胞瘤肿瘤发生的早期机制。这些结果表明，UHRF1在视网膜母细胞瘤中的肿瘤促进功能在很大程度上独立于其在DNA甲基化中的作用。
