The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2
Open accessAbstract
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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“Inhibition of histone deacetylase (HDAC) increases acetylation of H4 and disrupts the interaction between the locus and RNA polymerase II, leading to the suppression of PU.1 transcription in murine microglia [35, 36].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [36]
In the citing paper
“Valproic acid treatment, which selectively inhibits the catalytic activity of class I HDACs and induces proteasomal degradation of HDAC2, of primary adult human microglia reduces phagocytic capacity and expression of PU.1 and CD45, suggesting the its regulation of microglial phagocytosis via epigenetic mechanism [36-38].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [36]
In the citing paper
“Acetylation of histone H4 on the promoter and intron-1 region of the PU.1 locus are tightly regulated for allowing the interaction between the locus and RNA polymerase II.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [36]
In the citing paper
“suggesting the its regulation of microglial phagocytosis via epigenetic mechanism [36-38].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [36]
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Citations
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Metadata
- 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
- Venue
- The EMBO Journal
- Published
- 2003-07-01
- Volume
- 22
- Issue
- 13
- Pages
- 3411-3420
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- 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
- 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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