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]
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“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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“Similarly, HDAC6 inhibitors (ricolinostat, citarinostat) target cytoplasmic HDAC6, which stabilizes AR by deacetylating HSP90, showing improved tolerability profiles [102,103].”
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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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