Cited by 523Histone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathwaysGenomics and Chromatin Dynamics

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The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2

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Krämer, Oliver H., Zhu, Ping, Ostendorff, Heather P., Golebiewski, Martin, Tiefenbach, Jens, Peters, Marvin A., Brill, Boris, Groner, Bernd, Bach, Ingolf, Heinzel, Thorsten, Göttlicher, Martin·2003·The EMBO Journal

DOI 10.1093/emboj/cdg315PMC PMC165640

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Abstract

Histone-modifying enzymes play essential roles in physiological and aberrant gene regulation. Since histone deacetylases (HDACs) are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. Selective modulators of HDAC isoenzymes could serve as efficient and well-tolerated drugs. We show that HDAC2 undergoes basal turnover by the ubiquitin-proteasome pathway. Valproic acid (VPA), in addition to selectively inhibiting the catalytic activity of class I HDACs, induces proteasomal degradation of HDAC2, in contrast to other inhibitors such as trichostatin A (TSA). Basal and VPA-induced HDAC2 turnover critically depend on the E2 ubiquitin conjugase Ubc8 and the E3 ubiquitin ligase RLIM. Ubc8 gene expression is induced by both VPA and TSA, whereas only TSA simultaneously reduces RLIM protein levels and therefore fails to induce HDAC2 degradation. Thus, poly-ubiquitination and proteasomal degradation provide an isoenzyme-selective mechanism for downregulation of HDAC2.

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Authors: Krämer, O. H., Zhu, P., Ostendorff, H. P., Golebiewski, M., Tiefenbach, J., Peters, M. A., Brill, B., Groner, B., Bach, I., Heinzel, T., & Göttlicher, M.
Affiliations: Georg Speyer Haus (DE)
Universität Hamburg (DE)
Corresponding author: Heinzel, Thorsten
Göttlicher, Martin
ORCID: Krämer, Oliver H.
Golebiewski, Martin
Bach, Ingolf
Heinzel, Thorsten
Göttlicher, Martin
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2003-07-01
Volume: 22
Issue: 13
Pages: 3411-3420
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1093/emboj/cdg315
PMC: PMC165640
OpenAlex: W2106775330
Cited by: 523
References: 41
Citations by year: 2026: 5 · 2025: 8 · 2024: 14 · 2023: 13 · 2022: 25 · 2021: 16 · 2020: 19 · 2019: 20 · 2018: 27 · 2017: 26 · 2016: 30 · 2015: 19 · 2014: 27 · 2013: 33 · 2012: 29
FWCI: 8.96
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Site cant be reached (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: valproic acid, HDAC2, histone deacetylase inhibitors, proteasomal degradation, ubiquitin-proteasome system, RLIM, polyubiquitination, trichostatin A, class I HDACs, protein turnover
MeSH terms: Animals, Base Sequence, Cells, Cultured, Cysteine Endopeptidases, Enzyme Inhibitors, Female, Hydrolysis, Hydroxamic Acids, Multienzyme Complexes, Valproic Acid, DNA Primers, Ubiquitin, Proteasome Endopeptidase Complex, Mice, Histone Deacetylase Inhibitors

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The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2

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