Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

Abstract

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study.

Figure 1

Class I HDAC expression in prostate tissue. (A) Moderate HDAC3 staining was evident in the nuclei of luminal epithelial cells (arrows) of normal prostate glands, whereas the majority of basal epithelial cells revealed only weak HDAC positivity (arrowhead). Note occasional moderate HDAC3 expression in prostate stroma cells. Inset: autonomous neural plexus cells exhibiting strong HDAC3 nuclear staining. (B) High-grade PIN (arrows) with strong nuclear positivity for HDAC2. (C) Microacinar prostate adenocarcinoma with only few tumour cell nuclei showing moderate expression of HDAC2. This case was scored as HDAC2 low. (D) Prostate carcinoma with moderate nuclear expression of HDAC1 (arrows) in approximately 70% of tumour cells. (E) Adenocarcinoma with homogenous strong nuclear expression of HDAC2 (arrows). Note adjacent normal prostate gland (arrowheads). (F) Perineural microacinar neoplastic infiltrates exhibiting strong HDAC3 expression in approximately 70% of tumour cell nuclei.

Figure 2

Kaplan–Meier survival curves in dependence of Gleason grade and class I HDAC expression patterns. PSA-relapse-free survival in dependence of (A) Gleason grade, (B) HDAC1, (C) HDAC2 and (D) HDAC3 expression. P-values were calculated with the log-rank test.