Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of androgen sensitivity in hormone refractory cancer of the prostate

Objectives: To examine the effect of androgen treatment upon histone deacetylase 4 (HDAC4) localisation and, thus, enzymatic function in androgen sensitive prostate cancer (CaP) models. To study HDAC4 expression in benign prostatic hyperplasia, primary and hormone refractory (HR) CaP and to investigate the involvement of histone deacetylase activity in the development of the androgen insensitive phenotype. Methods: Immunohistochemical staining of prostate sections of both benign tissue and primary and hormone relapsed prostate cancer, as well as of the CWR22 mouse xenograft model, and indirect quantitative immunofluorescence staining of endogenous HDAC4 in LNCaP cells. Results: HDAC4 is recruited to the nuclei of HR cancer cells, where it may exert an inhibitory effect on differentiation and contribute to the development of the aggressive phenotype of late stage CaP. The above may result from,the loss of androgen responsiveness characterising HR CaP, since HDAC4 nuclear localisation is regulated by androgens in androgen responsive systems (i.e. LNCaP, CWR22) reflecting earlier phase disease. Conclusions: HDAC4 may contribute to the development of HR CaP and, therefore, constitute a potential therapeutic target, particularly in the most lethal phase of androgen independence. (C) 2003 Elsevier B.V. All rights reserved.