HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis
Open accessAbstract
HDAC6-selective inhibitors represent promising new cancer therapeutic agents, but their precise mechanisms of action are not well understood. In particular, p53's role in HDAC6 inhibitor-induced effects has not been fully elucidated. In this study, we show that an HDAC6-selective inhibitor, A452, increased wild-type p53 levels by destabilizing MDM2, but decreased mutant p53 by inducing MDM2 and inhibiting Hsp90-mutant p53 complex formation. Interestingly, HDAC6 levels inversely correlated with p53 acetylation at lysines 381/382 associated with p53 functional activation. A452 blocked HDAC6 nuclear localization, resulting in increased levels of acetylated p53 at Lys381/382. HDAC6 bound to the C-terminal region of p53 via its deacetylase domain. A452 disrupted the HDAC6-Hsp90 chaperone machinery via Hsp90 acetylation and degradation. Furthermore, it chemosensitized cancer cells to the Hsp90 inhibitor 17-AAG. Overall, silencing of HDAC6 showed similar effects. These findings suggest that the anticancer action of HDAC6 inhibitors requires p53 and Hsp90 and targeting of HDAC6 may represent a new therapeutic strategy for cancers regardless of p53's mutation status.
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HDAC6 has been associated with deacetylation of several cytosolic substrates including α-tubulin and p53.
“the class IIb isozyme, HDAC6, has been associated with deacetylation of several cytosolic substrates including a -tubulin and p53 (Hubbert et al., 2002; Zhang et al., 2003; Ryu et al., 2017).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Ryu et al., 2017
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- Authors
- Ryu, H.-W., Shin, D.-H., Lee, D. H., Choi, J., Han, G., Lee, K. Y., & Kwon, S. H.
- Affiliations
- Yonsei University (KR)
- Corresponding author
- Kwon, So Hee
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 391
- Pages
- 162-171
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2585821909
- Cited by
- 82
- References
- 49
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 12 · 2021: 11 · 2020: 12 · 2019: 10 · 2018: 4 · 2017: 7
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministry of Education, Science and Technology (2014R1A1A2054026)
- National Research Foundation of Korea
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- HDAC6, p53 acetylation, HDAC6 inhibitors, MDM2, HSP90, HSP90 acetylation, chemosensitization, 17-AAG, TP53 mutation
- MeSH terms
- Histone Deacetylases, Humans, Lysine, Tumor Suppressor Protein p53, Apoptosis, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors
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