Genome-wide Loss-of-Function Screen Reveals an Important Role for the Proteasome in HDAC Inhibitor-Induced Apoptosis
Open accessAbstract
Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.
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RAD23B was upregulated following C1A treatment.
“Of note is the upregulation of RAD23B that was recently proposed as a predictive marker of response to HDACIs generally (Fotheringham et al, 2009).”
From A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth (2013) · cites this paper as Fotheringham et al, 2009
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- Authors
- Fotheringham, S., Epping, M. T., Stimson, L., Khan, O., Wood, V., Pezzella, F., Bernards, R., & La Thangue, N. B.
- Affiliations
- University of Oxford (GB)
- The Netherlands Cancer Institute (NL)
- Cancer Research UK (GB)
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 15
- Issue
- 1
- Pages
- 57-66
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2051890772
- Cited by
- 138
- References
- 26
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 2 · 2021: 8 · 2020: 12 · 2019: 1 · 2018: 4 · 2017: 3 · 2016: 12 · 2015: 7 · 2014: 14 · 2013: 9 · 2012: 19
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research UK (13058)
- Medical Research Council
- 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 › Protein Degradation and Inhibitors
- Keywords
- proteasome, histone deacetylase inhibitors, apoptosis, HR23B, protein acetylation, proteasome inhibitors
- MeSH terms
- Animals, Biopsy, DNA-Binding Proteins, Drug Evaluation, Preclinical, Enzyme Inhibitors, Histone Deacetylases, Skin Neoplasms, Substrate Specificity, Gene Expression Regulation, Neoplastic, Lymphoma, T-Cell, Cutaneous, Genome, Apoptosis, Mice, Knockout, RNA Interference, Cell Line, Tumor, Proteasome Endopeptidase Complex, Mice, Histone Deacetylase Inhibitors
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