Department of Structural and Functional Biology, University of Insubria, Via A da Giussano 12, Busto Arsizio, Italy.
Oncogene. 2012 Nov 15;31(46):4878-87. doi: 10.1038/onc.2011.641. Epub 2012 Feb 13.
Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (P < 0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.
肿瘤抑制基因的表观遗传沉默是细胞转化和肿瘤进展中涉及的重要机制。SET 和 RING 指结构域蛋白 UHRF1 可能是不同表观遗传途径之间的重要联系。在这里，我们报告 UHRF1 在人类前列腺肿瘤中经常过表达，并在前列腺癌发病机制和进展中具有重要作用。通过微阵列和免疫组织化学分析人类前列腺癌样本显示，大约一半的病例中 UHRF1 的表达增加。此外，在具有器官局限型前列腺肿瘤的患者中，UHRF1 表达与前列腺切除术后的总生存时间缩短相关（P < 0.0001）。UHRF1 表达与几种肿瘤抑制基因的表达降低以及组蛋白甲基转移酶（HMT）EZH2 的表达呈正相关，这在前列腺肿瘤和细胞系中均有体现。UHRF1 敲低降低了前列腺癌细胞的增殖、集落形成能力和非锚定依赖性生长。UHRF1 的耗竭导致几个肿瘤抑制基因的重新激活。UHRF1 耗竭后基因的重新激活与组蛋白 H3K9 甲基化、乙酰化和 DNA 甲基化的变化以及沉默基因启动子上 H3K9 HMT Suv39H1 结合的受损有关。共免疫沉淀实验表明 UHRF1 与 Suv39H1 之间存在直接相互作用。我们的数据支持这样一种观点，即 UHRF1 与 Suv39H1 和 DNA 甲基转移酶一起，有助于前列腺肿瘤中的表观遗传基因沉默。这可能代表与 EZH2 催化的 H3K27 甲基化平行且收敛的途径，以协同促进肿瘤抑制基因的失活。UHRF1 的失调表达参与了前列腺癌的发病机制，并且可能代表了一种有用的标志物，可以将惰性癌症与具有致命进展高风险的癌症区分开来。
