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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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Histone H1 expression in human prostate cancer tissues and cell lines
Sato, S., Takahashi, S., Asamoto, M., Nakanishi, M., Wakita, T., Ogura, Y., Yatabe, Y., & Shirai, T. (2011) · Pathology International · doi:10.1111/j.1440-1827.2011.02755.x · Cited by 23
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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
“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
“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
Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment
Zhou, M., Zheng, H., Li, Y., Huang, H., Min, X., Dai, S., Zhou, W., Chen, Z., Xu, G., & Chen, Y. (2021) · Aging · doi:10.18632/aging.202554 · Cited by 20
“Interestingly, HDAC6 has been shown to affect the acetylation status of heat shock protein 90 (HSP90), which is a key androgen receptor chaperone [12].”
Huang, E., Zhao, Y., Chen, G., Baek, S. J., McEntee, M. F., Minkin, S. C., Biggerstaff, J., & Whelan, J. N. (2014) · BMC Complementary and Alternative Medicine · doi:10.1186/1472-6882-14-68 · Cited by 19
“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
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
“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.”
BackgroundInfluentialSu, F., Corrêa, B., Luo, J., Vêncio, R. Z. N., Pascal, L. E., & Wang, Z. (2013) · Cancer Microenvironment · doi:10.1007/s12307-013-0132-4 · Cited by 16
Li, N., Tie, X., Liu, P., Zhang, Y., Ren, H., Gao, X., & Xu, Z. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.2.685 · Cited by 16
“, 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
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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).”
BackgroundMcCarty, M. F., Hejazi, J., & Rastmanesh, R. (2014) · Integrative Cancer Therapies · doi:10.1177/1534735414534728 · Cited by 14
“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…”
BackgroundMartinez, H. D., Hsiao, J. J., Jasavala, R. J., Hinkson, I. V., Eng, J. K., & Wright, M. E. (2011) · Genes & Cancer · doi:10.1177/1947601912436422 · Cited by 14
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Epigenetic Editing in Prostate Cancer: Challenges and Opportunities
Pacheco, M. B., Camilo, V., Henrique, R., & Jerónimo, C. (2021) · Epigenetics · doi:10.1080/15592294.2021.1939477 · Cited by 12
New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer
Godbole, A. M., & Njar, V. C. O. (2011) · Prostate Cancer · doi:10.1155/2011/918707 · Cited by 12
“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
Chow, C. C., & Simons, S. S. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00076 · Cited by 11
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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)
Li, M., Zhuang, Y., & Shan, B. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3667-0_6 · Cited by 8
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Targeting Epigenetics for the Treatment of Prostate Cancer: Recent Progress and Future Directions
Lin, J., Wang, C., & Kelly, W. K. (2013) · Seminars in Oncology · doi:10.1053/j.seminoncol.2013.04.010 · Cited by 7
Minireview: The Versatile Roles of Lysine Deacetylases in Steroid Receptor Signaling
Kadiyala, V., & Smith, C. L. (2014) · Molecular Endocrinology · doi:10.1210/me.2014-1002 · Cited by 5
The classical and updated models of androgen receptor nucleocytoplasmic trafficking.
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Phosphoprotein phosphatase 1-interacting proteins as therapeutic targets in prostate cancer
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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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