HDAC3 functions as a positive regulator in Notch signal transduction
Open accessAbstract
Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.
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Another non-histone target of HDAC3 is NICD1.
“Another non-histone target of HDAC3 is NICD1 (Notch1 intracellular domain).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Ferrante et al., 2020
HDAC3 deacetylates NICD1 and controls its stability to sustain Notch signaling.
“As described above for DNMT1, HDAC3 deacetylates NICD1 and controls its stability to sustain Notch signaling (Ferrante et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Ferrante et al., 2020
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References 80 · Cited by 50
- Authors
- Ferrante, F., Giaimo, B. D., Bartkuhn, M., Zimmermann, T., Close, V., Mertens, D., Nist, A., Stiewe, T., Meier-Soelch, J., Kracht, M., Just, S., Klöble, P., Oswald, F., & Borggrefe, T.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- German Cancer Research Center (DE)
- Philipps University of Marburg (DE)
- Rudolf Buchheim Institute of Pharmacology, University of Giessen, Schubertstrasse 81, 35392 Giessen, Germany
- Universität Ulm (DE)
- Corresponding author
- Oswald, Franz
- Borggrefe, Tilman
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-02-28
- Volume
- 48
- Issue
- 7
- Pages
- 3496-3512
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC7144913
- OpenAlex
- W3008185905
- Cited by
- 50
- References
- 80
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 2
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (Kr1143/7-3, KR1143/9-1, TRR81/2, SFB1021, SFB 1074/B02, JU 2859/2-1)
- Heisenberg program (BO 1639/5-1, SFB 1074/A03, OS 287/4-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- HDAC3, Notch signaling, Notch1 intracellular domain, protein stability, proteasomal degradation, histone acetylation, apicidin, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, Notch target genes, leukemia treatment
- MeSH terms
- Histone Deacetylase 3, Animals, Cell Line, Histone Deacetylases, Humans, Leukemia, Lysine, Mutation, Peptides, Cyclic, Signal Transduction, Cell Line, Tumor, Mice, Receptor, Notch1, Protein Stability, Histone Deacetylase Inhibitors
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