The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.
Open accessAbstract
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.
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“Furthermore, silencing of HDAC6 in these cells inhibits androgen-dependent and -independent cell growth, both in vitro and in a castrated nude mouse xenograft model (63).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [63]
In the citing paper
“Knockdown of HDAC6 in C4-2 cells inhibits the nuclear localization of endogenous AR and inhibits expression of PSA (63).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [63]
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1 retracted
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Gronemeyer, H., Gustafsson, J.-Å., & Laudet, V. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1551 · Cited by 1,285
HDAC6 Regulates Hsp90 Acetylation and Chaperone-Dependent Activation of Glucocorticoid Receptor
Kovacs, J. J., Murphy, P. J. M., Gaillard, S., Zhao, X., Wu, J.-T., Nicchitta, C. V., Yoshida, M., Toft, D. O., Pratt, W. B., & Yao, T.-P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.021 · Cited by 1,153
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Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Lin, A., Giuliano, C. J., Palladino, A. C., John, K. M., Abramowicz, C., Yuan, M. L., Sausville, E. L., Lukow, D. A., Liu, L., Chait, A. R., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw8412 · Cited by 769
Androgen receptors in hormone-dependent and castration-resistant prostate cancer
Shafi, A. A., Yen, A. E., & Weigel, N. L. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.07.003 · Cited by 435
“In addition to AR antagonists and approaches to further reduce levels of androgens, chaperone protein inhibitors (Hsp90), and histone deacetylase (HDAC) inhibitors to combat the reactivation of AR signaling that occurs in CRPC are being developed (Scher & Sawyers, 2005; Minucci & Pelicci, 2006; Rokhlin et al., 2006; A…”
BackgroundAldana-Masangkay, G. I., & Sakamoto, K. M. (2010) · BioMed Research International · doi:10.1155/2011/875824 · Cited by 388
“In a different study, knockdown of HDAC6 in prostate cancer (PCa) C4-2 cells led to the hyperacetylation of Hsp90, impaired ligand-independent nuclear localization of endogenous androgen receptor (AR), inhibited prostate-specific antigen (PSA) expression, and cell growth in the absence or presence of dihydrotestostero…”
BackgroundJackson, S. (2012) · Topics in current chemistry · doi:10.1007/128_2012_356 · Cited by 347
“Androgen receptor (AR) activity has also been shown to be affected by HDAC6 inhibition, thus suggesting that steroid receptors in general may require dynamic Hsp90 acetylation/deacetylation to attain their full function [180].”
BackgroundStructure, Function, and Regulation of the Hsp90 MachineryPreprint
Biebl, M. M., & Büchner, J. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034017 · Cited by 315
“Generally, acetylation and nitrosylation are considered to weaken the interaction of Hsp90 with clients, favoring their destabilization and degradation (Scroggins et al. 2007; Ai et al. 2009; Retzlaff et al. 2009; Zhang et al. 2010).”
Background
Metadata
- Authors
- Ai, J., Wang, Y., Dar, J. A., Liu, J., Liu, L., Nelson, J. B., & Wang, Z.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Wang, Zhou
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2009-12
- Volume
- 23
- Issue
- 12
- Pages
- 1963-1972
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC2796151
- OpenAlex
- W2091885586
- Cited by
- 126
- References
- 52
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 11 · 2020: 10 · 2019: 7 · 2018: 7 · 2017: 6 · 2016: 14 · 2015: 3 · 2014: 12 · 2013: 14 · 2012: 7
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA108675, P50CA090386, 1P50 CA90386)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK051193, 5R37DK51193)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- HDAC6, androgen receptor, castration-resistant prostate cancer, HSP90 acetylation, dihydrotestosterone, prostate-specific antigen, C4-2 cells, tumor xenografts, histone deacetylase
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Castration, Histone Deacetylases, Humans, Hydroxamic Acids, Male, Prostatic Neoplasms, Receptors, Androgen, Dihydrotestosterone, Blotting, Western, Gene Expression, Prostate-Specific Antigen, HSP90 Heat-Shock Proteins, Reverse Transcriptase Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Cell Line, Tumor, Immunoprecipitation, Cell Proliferation, Mice
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