Functional dissection of the role of UHRF1 in the regulation of retinoblastoma methylome
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Guangyan Kan1,2,*, Heng He1,*, Qi Zhao3, Xiubo Li1, Min Li1, Huasheng Yang1 and Jong Kyong Kim1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China
2Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510060, China
3Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
*These authors have contributed equally to the work
Jong Kyong Kim, email: [email protected]
Keywords: retinoblastoma, DNA methylation, UHRF1, global hypomethylation, tumorigenesis of murine retinoblastoma
Received: January 02, 2017 Accepted: March 21, 2017 Published: April 13, 2017
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.
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