HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer
Open Access
- 1 December 2009
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 23 (12), 1963-1972
- https://doi.org/10.1210/me.2009-0188
Abstract
The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa.Keywords
This publication has 51 references indexed in Scilit:
- HDAC6 Modulates Hsp90 Chaperone Activity and Regulates Activation of Aryl Hydrocarbon Receptor SignalingJournal of Biological Chemistry, 2009
- Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone functionMolecular Cancer Therapeutics, 2008
- DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐linesThe Prostate, 2007
- Principles for modulation of the nuclear receptor superfamilyNature Reviews Drug Discovery, 2004
- Molecular determinants of resistance to antiandrogen therapyNature Medicine, 2003
- Identification and Characterization of a Ligand-regulated Nuclear Export Signal in Androgen ReceptorJournal of Biological Chemistry, 2003
- 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts.2002
- Androgen Receptor Signaling in Androgen-Refractory Prostate CancerJNCI Journal of the National Cancer Institute, 2001
- Human HDAC7 Histone Deacetylase Activity Is Associated with HDAC3in VivoJournal of Biological Chemistry, 2001
- Studies on Prostatic Cancer: I. The Effect of Castration, Of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the ProstateCA: A Cancer Journal for Clinicians, 1972