Histone deacetylase inhibitor valproic acid suppresses the growth and increases the androgen responsiveness of prostate cancer cells

We identified the molecular target by histone deacetylase (HDAC) inhibitors for exploring their potential prostate cancer (PCa) therapy. Upon HDAC inhibitors-treatment, LNCaP cell growth was suppressed, correlating with increased cellular prostatic acid phosphatase (cPAcP) expression, an authentic protein tyrosine phosphatase. In those cells, ErbB-2 was dephosphorylated, histone H3/H4 acetylation and methylation increased and cyclin proteins decreased. In PAcP shRNA-transfected C-81 cells, valproic acid (VPA) efficacy of growth suppression was diminished. Further, VPA pre-treatment enhanced androgen responsiveness of C-81, C4-2 and MDA PCa2b-AI cells. Thus, cPAcP expression is involved in growth suppression by HDAC inhibitors in PCa cells, and VPA pre-treatments increase androgen responsiveness.

► HDAC inhibitors up-regulate the expression of cPAcP, a negative growth regulator. ► Increased cPAcP expression is associated with ErbB-2 dephosphorylation. ► cPAcP is involved in growth suppression by HDAC inhibitors in PCa cells. ► Valporic acid treatment enhances the androgen-responsiveness of PCa cells. ► Intermit HDAC inhibitor treatments may prolong androgen ablation therapy.