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Purpose: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue., Materials and Methods: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry., Results: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome., Conclusions: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis., Methods: Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels., Results: Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy., Conclusions: H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

Background/aim: To determine the role of global histone H3K9 and H4K20 methylation levels as prognostic parameters in patients with renal cell cancer (RCC)., Material and Methods: Global histone methylation levels were investigated in 193 RCC (including 142 clear cell (cc), 31 papillary (p), 10 chromophobe (ch) and 10 sarcomatoid (s) RCC), 10 oncocytomas and 30 benign renal specimens., Results: Histone modifications were mostly similar in the different histological subtypes (p>0.05); significant differences were observed for ccRCC vs. pRCC and pRCC vs. sRCC. Comparing the global H3K9 methylation levels of benign renal tissue with RCC H3K9me1 (histone H3 lysine 9 mono-methylation) (p<0.001), H3K9me2 (histone H3 lysine 9 di-methylation) (p=0.001) and H3K9me3 (histone H3 lysine 9 tri-methylation) (p<0.001) was significantly over-expressed in benign renal tissue. H3K9 and H4K20 methylation levels were positively correlated to pT-stage (p<0.005) and grading (p<0.05). In localized RCC (n=144), H3K9me1 levels showed a significant correlation with progression-free survival in the univariate model (p=0.034)., Conclusion: Global histone methylation levels may help to identify RCC patients with poor prognosis.

Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.

Objective: •To determine the role of global histone methylation as a prognostic parameter in patients with bladder cancer., Patients and Methods: •We used a tissue microarray with samples from patients with non-muscle-invasive bladder cancer (NMIBC; n= 161), muscle-invasive bladder cancer (MIBC, n= 127), normal urothelium (NU; n= 31) and bladder cancer metastases (METS; n= 31) to determine global histone methylation (me) levels at histone H3 lysine 4 (H3K4) and H4K20., Results: •Global histone modification levels (H3K4me1, H3K4me3, H4K20me1, H4K20me2, and H4K20me3) were lower in bladder cancer samples than in NU tissue •Global levels of H3K4me1, H4K20me1, H4K20me2 and H4K20me3 were decreasing from NU over NMIBC and MIBC to METS. •H4K20me1 levels were increased in patients with NMIBC with advanced pTstage and less differentiated bladder cancer. •In patients with MIBC, pTstage was negatively correlated with H3K4me1, H4K20me1 and H4K20me2 levels. •H4K20me3 levels were significantly correlated in a univariate and multivariate model with bladder cancer-specific mortality after radical cystectomy in patients with MIBC., Conclusion: •Global histone methylation levels may help to identify patients with bladder cancer with poor prognosis after radical cystectomy., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Epigenetic alterations play an important role in carcinogenesis. Recent studies have suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Global histone acetylation levels (histone H3 lysine 9 acetylation [H3K9Ac], histone H3 lysine 18 acetylation [H3K18Ac], total histone H3 acetylation [H3Ac] and total histone H4 acetylation [H4Ac]) were determined in patients with renal cell carcinoma (RCC) using immunohistochemistry in a tissue micro array with 193 RCC and 10 oncocytoma specimens. The histone acetylation pattern was not different among the diverse histological subtypes of RCC or oncocytoma samples. The H3Ac levels were inversely correlated with pT-stage (P = 0.005), distant metastasis (P = 0.036), Fuhrman grading (P = 0.001) and RCC progression (P = 0.029, hazard ratio 0.87). H4Ac deacetylation was correlated with pT-stage (P = 0.011) and grading (P = 0.029). H3K18Ac levels were an independent predictor of cancer-progression following surgery for localized RCC in the univariate (P = 0.001, hazard ratio 0.78) and multivariate (P = 0.005, hazard ratio 0.82) analysis. In conclusion, our study supports the concept of global histone modification levels as a universal cancer prognosis marker, and provides evidence for the use of histone deacetylases inhibitors as future drugs in the therapy of RCC., (© 2010 Japanese Cancer Association.)

Epigenetic alterations play an important role in carcinogenesis. Recent studies suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone H3 lysine 4 mono-methyl (H3K4me1), -di-methyl (H3K4me2) and -trimethyl (H3K4me3) patterns in renal cell carcinoma (RCC) using a tissue microarray with 193 RCC (including 142 clear cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC) and 10 oncocytoma specimens: H3K4me3 staining was more intense in papillary RCC, whereas H3K4me1 and H3K4me2 were similar in the diverse RCC subtypes. H3K4me2 and H3K4me3 levels were increased in oncocytoma. H3K4me1-3 levels were inversely correlated with Fuhrman grading, pT stage, lymph node involvement and distant metastasis. Progression-free survival and cancer-specific survival were shorter in patients with low levels of H3K4me1-3 in the univariate analysis, but we did not observe a significant correlation of a single modification in a multivariate model, which also included the established prognostic parameters TNM-stage and Fuhrman grade. In comparison, the H3K4me score, which combined staining levels of the H3K4 modifications, was an independent predictor of RCC progression-free survival. Our study on H3K4 methylation supports the concept of global histone modifications as potential cancer prognosis markers.

Purpose: Epigenetic alterations such as DNA methylation and histone modifications play important roles in carcinogenesis. It was reported that global histone modification patterns are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone lysine (H(x)K(y)) and histone acetyl (H(x)Ac) modifications in prostate tissue., Materials and Methods: A tissue microarray with 113 prostate cancer (PCA), 23 non-malignant prostate tissues was stained with antibodies against H3K4 mono-(H3K4me1), di-(H3K4me2), tri-(H3K4me3) methylation, H3K9me1, H3K9me2, H3K9me3, H3 and H4 pan-acetylation (H3Ac, H4Ac). We also analyzed H3K4 methylation in patients with advanced PCA (hormone-refractory PCA-HRPC, n = 34; hormone-dependent PCA, n = 30). Sections were scored according the staining intensity and the proportion of epithelial cells showing nuclear staining., Results: H3K4me1, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in PCA compared to non-malignant prostate tissue. H3Ac and H3K9me2 levels allowed discrimination of PCA and non-malignant prostate tissue highly specifically (>91%) and sensitively (>78%) as determined via ROC analyses (AUC >0.91). Histone lysine methylation and histone acetylation marks were correlated with clinical-pathological parameters (i.e., digital rectal examination, preoperative PSA, pT-stage, lymph node metastasis, Gleason score). In addition, H3K4me1 was a significant predictor of PSA recurrence following radical prostatectomy. H3K4me1, H3K4me2, and H3K4me3 levels were significantly increased in HRPC., Conclusions: Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA., ((c) 2009 Wiley-Liss, Inc.)

What's known on the subject? and What does the study add? Epigenetic alterations are important during carcinogenesis, and earlier studies suggested that global histone modification levels are predictive for patients' outcome in various tumor entities. We demonstrate that H3K27me1 and H3K27me3 are markers of progression-free survival in patients with renal cell carcinoma. OBJECTIVE • To evaluate if histone H3 lysine 27 (H3K27) methylation plays a role in renal cell carcinoma (RCC) tissue and whether its expression is a predictor of cancer recurrence in RCC. MATERIALS AND METHODS • A tissue microarray (TMA) with 193 RCC specimens (comprising 142 clear-cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC), 10 oncocytoma tissue specimens and a TMA with 30 benign renal tissue samples were stained with antibodies against H3K27-monomethyl (H3K27me1), H3K27-dimethyl (H3K27me2) and H3K27-trimethyl (H3K27me3). • Sections were scored according to staining intensity and the proportion of epithelial cells showing nuclear staining. • H3K27 methylation levels were correlated with established clinical-pathological variables (tumour-node-metastasis [TNM] stage, Fuhrman grade) and progression-free/cancer-specific survival. RESULTS • H3K27me1/-me2/-me3 staining was significantly more intense in papillary RCC then in clear-cell RCC. • H3K27me3 levels were higher in oncocytoma than in RCC. • H3K27me1/-me2/-me3 methylation levels were inversely correlated with Fuhrman grading and pT-stage. • Global H3K27me1/-me2/-me3 methylation levels were always higher in benign renal tissue than in RCC with tumour relapse (H3K27me1 P < 0.001, H3K27me2 P= 0.032, H3K27me3 P= 0.004). • Progression-free survival was shorter in patients with lower levels of H3K27me1 and H3K27me3 in the univariate analysis. The newly created H3K27me score (combining the staining levels of the single modifications) was a significant and independent predictor of RCC progression-free survival. CONCLUSION • The present study on H3K27-methylation supports the hypothesis that global histone modifications are potential markers of cancer prognosis in RCC. One reason could be that decreased H3K27 indicates transcriptional activation and therefore predicts cancer activation. [ABSTRACT FROM AUTHOR]

Gene silencing by promoter DNA hypermethylation is common in PCA. The role of HXKy methylation as an up-/downstream or parallel silencing mechanism is not yet clear. We analyzed HXKy methylation at gene sites that are aberrantly DNA-methylated in PCA (i.e. GSTP1, RARβ, APC and PTGS2). Cancerous (PC3, DU145, LNCaP) and benign prostate hyperplasia (BPH1) cell lines were studied using chromatin immunoprecipitation and methylation specific PCR. Gene expression was analyzed using quantitative RT-PCR. In PCA, histone modifications characteristic of gene repression (di-/tri-methylated H3K9, H3K27, H4K20) were predominantly observed at the studied gene sites and paralleled aberrant DNA hypermethylation. In BPH, no aberrant DNA hypermethylation and mostly histone modifications supporting active gene expression (H3K4, H3K79 di-/tri methylation) were seen at the respective gene sites. Mono-methylated H3K4 and H3K9 modifications that have moderate effects on gene expression were frequent in both PCA and BPH. PC3 cells grown in the presence of the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (aza) resulted in DNA demethylation and moderate gene reexpression whereas repressive HXKy di-methylation increased 1.5-3 fold and tri-methylation was mostly unchanged. Removal of aza reverses gene expression. These findings suggest that HXKy methylation is upstream to DNA hypermethylation in PCA. [ABSTRACT FROM AUTHOR]