Roy Castle Lung Cancer Research Programme, University of Liverpool, Department of Clinical and Molecular Cancer Medicine, Liverpool, United Kingdom.
Cancer. 2011 Mar 1;117(5):1027-37. doi: 10.1002/cncr.25531. Epub 2010 Nov 8.
The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear.
mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells.
All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P = .005) and RASSF1 promoters (P = .034), and the relationship with a combined epigenotype was even stronger (P = 2.3 × 10(-4) ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties.
Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.
UHRF1 基因在 DNA 甲基化维持中具有重要作用，但它在原发性人类癌症中肿瘤抑制基因高甲基化中的作用尚不清楚。
通过定量聚合酶链反应评估 105 例原发性非小细胞肺癌中 UHRF1、DNMT1、DNMT3A、DNMT3B 和 E2F1 的 mRNA 表达水平。通过焦磷酸测序检测 CDKN2A 和 RASSF1 启动子的甲基化状态。在 A549 肺腺癌细胞中用短发夹 RNA 敲低 UHRF1。
4 种基因在肺癌组织中均呈协同过表达，其表达与 E2F1 相关。肿瘤组织中 UHRF1 表达较高与 CDKN2A（P=0.005）和 RASSF1 启动子的高甲基化相关（P=0.034），与联合表型的相关性更强（P=2.3×10（-4））。当 UHRF1 在 A549 肺腺癌细胞中被敲低时，RASSF1、CYGB 和 CDH13 启动子的甲基化水平较低。此外，UHRF1 敲低克隆显示增殖减少和迁移能力降低。
我们的数据表明，UHRF1 是一个关键的表观遗传开关，通过维持肿瘤抑制基因启动子的高甲基化状态，控制非小细胞肺癌中的细胞周期。因此，UHRF1 应与 DNMTs 一起被视为癌症治疗和/或治疗分层的潜在靶点。
