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Cited by 129Prostate Cancer Treatment and ResearchHistone Deacetylase Inhibitors ResearchHeat shock proteins research

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.

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Ai, Junkui, Wang, Yujuan, Dar, Javid A., Liu, June, Liu, Lingqi, Nelson, Joel B., Wang, Zhou·2009·Molecular Endocrinology
DOI 10.1210/me.2009-0188PMC PMC2796151
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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.

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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…”
    Background

  • The Role of HDAC6 in Cancer

    Aldana-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…”
    Background

  • Hsp90: Structure and Function

    Jackson, 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].”
    Background

  • Structure, 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).”
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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
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2009-12
Volume
23
Issue
12
Pages
1963-1972
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2009-0188
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
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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