Global levels of histone modifications predict prostate cancer recurrence.
OBJECTIVE
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.


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.
Ellinger
Jörg
J
Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Bonn, Germany. joerg.ellinger@ukb.uni-bonn.de
Kahl
Philip
P
von der Gathen
Johannes
J
Rogenhofer
Sebastian
S
Heukamp
Lukas C
LC
Gütgemann
Ines
I
Walter
Bernhard
B
Hofstädter
Ferdinand
F
Büttner
Reinhard
R
Müller
Stefan C
SC
Bastian
Patrick J
PJ
von Ruecker
Alexander
A
D014408:Biomarkers, Tumor / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology
D014408:Biomarkers, Tumor; D006657:Histones