Hoffmann Michele J, Engers Rainer, Florl Andrea R, Otte Arie P, Muller Mirko, Schulz Wolfgang A
1Department of Urology; Heinrich Heine University; Düsseldorf, Germany
Cancer Biol Ther. 2007 Sep;6(9):1403-12. doi: 10.4161/cbt.6.9.4542.
The polycomb proteins BMI-1, EZH2, and SIRT1 are characteristic components of the PRC1, PRC2, and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate cancer progression, whereas BMI-1 and SIRT1 are not well investigated. Like EZH2 expression, DNA methylation alterations escalate in higher stage prostate cancers, raising the question whether these epigenetic changes are related. Expression of EZH2, BMI-1, SIRT1, and the DNA methyltransferases DNMT1 and DNMT3B measured by qRT-PCR in 47 primary prostate cancers was compared to APC, ASC, GSTP1, RARB2, and RASSF1A hypermethylation and LINE-1 hypomethylation. SIRT1 and DNMT3B were overexpressed in cancerous over benign tissues, whereas BMI-1 was rather downregulated and DNMT1 significantly diminished. Nevertheless, cancers with higher DNMT1 and BMI-1 expression had worse clinical characteristics, as did those with elevated EZH2. In particular, above median DNMT1 expression predicted a worse prognosis. EZH2 and SIRT1 overexpression were well correlated with increased MKI67. Immunohistochemistry confirmed limited EZH2 and heterogeneous DNMT3B overexpression and explained the decrease in BMI-1 by pronounced heterogeneity among tumor cells. EZH2 overexpression, specifically among all factors investigated, was associated with more frequent hypermethylation, in particular of GSTP1 and RARB2, and also with LINE-1 hypomethylation. Our data reveal complex changes in the composition of polycomb repressor complexes in prostate cancer. Heterogeneously expressed BMI-1 and slightly increased EZH2 may characterize less malignant cancers, whereas more aggressive cases express both at higher levels. SIRT1 appears to be generally increased in prostate cancers. Intriguingly, our data suggest a direct influence of increased EZH2 on altered DNA methylation patterns in prostate cancer.
多梳蛋白BMI-1、EZH2和SIRT1分别是PRC1、PRC2和PRC4抑制复合物的特征性组成成分，这些复合物可对染色质进行修饰。此外，EZH2可通过与DNA甲基转移酶直接相互作用来影响DNA甲基化。在前列腺癌进展过程中EZH2表达增加，而BMI-1和SIRT1的研究尚不充分。与EZH2表达情况类似，DNA甲基化改变在更高分期的前列腺癌中更为严重，这就引发了这些表观遗传变化是否相关的问题。通过qRT-PCR检测了47例原发性前列腺癌中EZH2、BMI-1、SIRT1以及DNA甲基转移酶DNMT1和DNMT3B的表达，并将其与APC、ASC、GSTP1、RARB2和RASSF1A的高甲基化以及LINE-1的低甲基化情况进行比较。SIRT1和DNMT3B在癌组织中相对于良性组织呈过表达，而BMI-1表达下调，DNMT1显著减少。然而，DNMT1和BMI-1表达较高的癌症具有更差的临床特征，EZH2表达升高的癌症也是如此。特别是，DNMT1表达高于中位数预示着预后更差。EZH2和SIRT1的过表达与MKI67增加密切相关。免疫组织化学证实EZH2表达有限且DNMT3B过表达存在异质性，并解释了由于肿瘤细胞间明显的异质性导致BMI-1降低的原因。EZH2过表达，特别是在所研究的所有因素中，与更频繁的高甲基化相关，尤其是GSTP1和RARB2的高甲基化，也与LINE-1的低甲基化相关。我们的数据揭示了前列腺癌中多梳抑制复合物组成的复杂变化。异质性表达的BMI-1和略有增加的EZH2可能是恶性程度较低癌症的特征，而侵袭性更强的病例二者表达水平均较高。SIRT1在前列腺癌中似乎普遍增加。有趣的是，我们的数据表明EZH2增加对前列腺癌中DNA甲基化模式改变有直接影响。
