Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

Abstract

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.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013). DNMT3B may regulate epigenetic events to facilitate CRPC development (Hoffmann et al ., 2007). Collectively, evidence supports an association of SigMuc1NW with PC recurrence.…”

Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo

“…Furthermore, EZH2 can also control CpG methylation through direct physical contact with DNA methyltransferases. 33,34 Figure 4. effect of eZh2 knockdown on cisplatin sensibility in vivo. (a) Representative immunostaining for eZh2 and h3K27me3 in sheZh2 tumor xenografts and shVector tumor xenografts.…”

Genome-wide DNA Methylation Events in TMPRSS2–ERG Fusion-Negative Prostate Cancers Implicate an EZH2-Dependent Mechanism with miR-26a Hypermethylation

“…The polycomb group protein EZH2 is responsible for silencing of homeobox (HOX) genes through H3K27 methylation during tissue development (13)(14)(15), and it links histone modifi cations to DNA methylation as EZH2 target genes may consecutively become hypermethylated ( 16,17 ). In prostate cancer, aberrant DNA methylation is found to be associated with altered EZH2 expression, correlates with tumor progression, and is proposed to be one of the earliest events in oncogenesis ( 12, 13 , 15 , 18-20 ).…”