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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Silencing of HDAC6 in C4-2 cells inhibits androgen-dependent and androgen-independent cell growth in vitro and in a castrated nude mouse xenograft model.
“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]
Knockdown of HDAC6 in C4-2 cells inhibits nuclear localization of endogenous androgen receptor and inhibits expression of PSA.
“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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“In addition, HDAC6 may increase AR stability by deacetylating its chaperone protein HSP-90 (Ai et al., 2009). HDAC6may also function in the transport of lysosomes to themicrotubule organizing center (MOC), as HDAC6 knockdown produces dispersion of lysosomes from the MOC. In a study by Iwata et al. (2005), shRNAmediate…”
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“In brief, the LNCaP andC4–2 cells were incubated in RPMI supplemented with 5% CSS for 2 days, and then treated with AR antagonists in the presence of 10 nM or 1 nMDHT for 2 days, respectively (47).”
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“The acetylation of HSP90 results in a destabilization of the AR and subsequently in its degradation by the proteasome [90].”
BackgroundCurriculum vitae of HDAC6 in solid tumors
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“Recent studies on C4-2 cells, and C4-2 xenograft tumour established in castrated but not in testes-intact nude mice, suggested that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSPC1 acetylation [33].”
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“AR forms a heteromeric complex with two molecules of Hsp90, which has been shown to participate in regulating the stability of free AR [14].”
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“In addition, 17-AAG prevented nuclear localization of androgen receptor in the xenograft tumors [19].”
BackgroundDual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90)
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“expression of HDAC6 is considered a survival marker and correlated with a positive response to endocrine treatment in ER-positive breast cancer [14, 15].”
BackgroundResultGlucocorticoid receptor cofactors as therapeutic targets
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“HDAC6 knockdown causes a 10-fold right shift in the dose– response curve for dihydrotestosterone-induced growth of C4-2 androgen-resistant prostate cancer cells and reduces the growth of xenografts [34].”
Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy
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“deacetylation of HSP90 [64].”
SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells
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“SFN was reported to elicit AR degradation via intracellularly forming HDAC6-inhibiting NAC conjugate (Gibbs et al., 2009) and HDAC6 is known to modulate AR hypersensitivity and nuclear localization in CRPC (Ai et al., 2009).”
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“Indeed, HSP-90 inhibitors are known to target AR for proteasomal degradation (46).”
BackgroundThe Role of Alcohol-Induced Golgi Fragmentation for Androgen Receptor Signaling in Prostate Cancer
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“Previous studies showed that HDAC6 can regulate HSP90 acetylation [27] and that HSP90 deacetylation by HDAC6 is required for androgen-independent nuclear localization and activation of AR [28], suggesting that HDAC6 inhibition could also delay the progression of prostate cancer to castration-resistance.”
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The non-canonical mechanism of ER stress-mediated progression of prostate cancer
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Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer
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“It forms a chaperone complex with AR and helps in establishing a ligand-binding conformation of AR [84].”
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“To test the role of androgen/AR signaling in KLF5 transcription, we measured KLF5 expression in two androgen-responsive PCa cell lines, LNCaP and C4-2B, in hormone-free medium (RIPA1640 medium supplemented with charcoal-stripped bovine fetal serum) treated with varying concentrations of R1881, a synthetic androgen, sp…”
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“pression by approximately 50% and that androgen hypersensitivity depends on HDAC6-controlled Hsp90 acetylation/deacetylation and regulation of AR (28).”
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Histone H1 expression in human prostate cancer tissues and cell lines
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“This did not come as a surprise because molecules involved in AR transcription such as histones [64], the chaperone HSP90 [65], and AR itself [66, 67] are known substrates for acetylation/deacetylation.”
InfluentialLiu, Z., Cai, Y., Yang, Y. Z., Li, A., Bi, R., Wang, L., Shen, X., Wang, W., Jia, Y., Yu, B., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5108 · Cited by 22 · see citing works
“Histone deacetylase 6 (HDAC6) is involved in the aggresomal degradation of ubiquitinated proteins and contributes to the sensitivity of HDAC inhibitors (HDACi) [9].”
BackgroundInfluentialTargeting prostate cancer cells with enzalutamide‐HDAC inhibitor hybrid drug 2‐75
Hu, W., Xu, L., Chen, B., Ou, S., Muzzarelli, K. M., Hu, D., Li, Y., Yang, Z., Griend, D. J. V., Prins, G. S., et al. (2019) · The Prostate · doi:10.1002/pros.23832 · Cited by 22 · see citing works
“tion assisted by histone deacetylases (HDACs) also play critical roles in sustained AR signaling.(6,7) While this highlights a rationale for using”
Uba, A. İ., & Yelekçi, K. (2018) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2018.10.016 · Cited by 22 · see citing works
Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment
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“Interestingly, HDAC6 has been shown to affect the acetylation status of heat shock protein 90 (HSP90), which is a key androgen receptor chaperone [12].”
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“Ai J, Wang Y, Dar JA, Liu J, Liu L, Nelson JB, Wang Z: HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.”
InfluentialJadhavar, P. S., Ramachandran, S. A., Riquelme, E., Gupta, A., Quinn, K. P., Shivakumar, D., Ray, S. S., Zende, D., Nayak, A. K., Miglani, S. K., et al. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.09.058 · Cited by 18 · see citing works
Dar, J. A., Masoodi, K. Z., Eisermann, K., Isharwal, S., Ai, J., Pascal, L. E., Nelson, J. B., & Wang, Z. (2014) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.03.004 · Cited by 16 · see citing works
“Our results showed that the region of a.a. 294–556 was required for androgen-independent AR nuclear localization whereas a.a. 1–293 mediates Hsp90 regulation of AR nuclear localization in CRPC cells.”
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“, 2009), prostate cancer (Ai et al., 2009), multiple myeloma (Hideshima et al.”
BackgroundConditional deletion of ELL2 induces murine prostate intraepithelial neoplasia
Pascal, L. E., Masoodi, K. Z., Liu, J., Qiu, X., Song, Q., Wang, Y.-J., Zang, Y.-C., Yang, T.-J., Wang, Y., Rigatti, L. H., et al. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0112 · Cited by 16 · see citing works
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“Treatment with HDAC6-inhibitors induces hyperacetylation and inhibits ATP-binding and chaperone-function of Hsp90, resulting in polyubiquitination and proteasomal degradation of HSP90-client proteins, including HDAC6 itself, p53 and androgen receptor (AR) (Ai et al., 2009).”
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“Hsp90’s chaperone activity is impeded by acetylations that are reversed by HDAC6(111); inhibition of the latter has been shown to decrease AR expression and activity in prostate cancer cells.(112,113) Intriguingly, the crucifera-derived phase 2 inducer sulforaphane has been reported to inhibit HDAC6 and thereby destab…”
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Epigenetic Editing in Prostate Cancer: Challenges and Opportunities
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New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer
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“demonstrated that inactivation of HDAC6 inhibited AR nuclear localization and subsequent transactivation in PC and mouse embryonic fibroblast (MEF) cells [87].”
BackgroundStructure-Based Discovery of Hsp90/HDAC6 Dual Inhibitors Targeting Aggressive Prostate Cancer
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“Additionally, SBI-46 possessed potent anti-HDAC activity against HDACs 1 and 6; the two HDAC isoforms were suggested to be relevant for PCa growth [13,23,24].”
BackgroundAn Approach to Greater Specificity for Glucocorticoids
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Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway
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Analysis of Expression and Functions of Histone Deacetylase 6 (HDAC6)
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- 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
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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