Global levels of histone modifications predict prostate cancer recurrence

• Published in: The Prostate Vol. 70; no. 1; pp. 61 - 69
• Main Authors: Ellinger, Jörg, Kahl, Philip, von der Gathen, Johannes, Rogenhofer, Sebastian, Heukamp, Lukas C., Gütgemann, Ines, Walter, Bernhard, Hofstädter, Ferdinand, Büttner, Reinhard, Müller, Stefan C., Bastian, Patrick J., von Ruecker, Alexander
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2010
• Subjects: Biomarkers, Tumor - metabolism; Cohort Studies; Disease Progression; epigenetics; histone; Histones - metabolism; Humans; Male; methylation; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Predictive Value of Tests; prognosis; prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21038

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 (HxKy) and histone acetyl (HxAc) 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. Prostate 70: 61–69, 2010. © 2009 Wiley‐Liss, Inc.