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Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells
Open accessAbstract
Polycomb-repressive complex 2 (PRC2)-mediated histone methylation plays an important role in aberrant cancer gene silencing and is a potential target for cancer therapy. Here we show that S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) induces efficient apoptotic cell death in cancer cells but not in normal cells. We found that DZNep effectively depleted cellular levels of PRC2 components EZH2, SUZ12, and EED and inhibited associated histone H3 Lys 27 methylation (but not H3 Lys 9 methylation). By integrating RNA interference (RNAi), genome-wide expression analysis, and chromatin immunoprecipitation (ChIP) studies, we have identified a prominent set of genes selectively repressed by PRC2 in breast cancer that can be reactivated by DZNep. We further demonstrate that the preferential reactivation of a set of these genes by DZNep, including a novel apoptosis affector, FBXO32 , contributes to DZNep-induced apoptosis in breast cancer cells. Our results demonstrate the unique feature of DZNep as a novel chromatin remodeling compound and suggest that pharmacologic reversal of PRC2-mediated gene repression by DZNep may constitute a novel approach for cancer therapy.
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“The discovery of deazaneplanocin A (DZNep) is the first attempt to inhibit EZH2 function, which could effectively deplete EZH2, SUZ12, and EED at cellular levels [156].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [156]
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Metadata
- Authors
- Tan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., Karuturi, R. K. M., Tan, P. B. O., Liu, E. T., & Yu, Q.
- Affiliations
- Genome Institute of Singapore (SG)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Duke-NUS Medical School (SG)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-04-16
- Volume
- 21
- Issue
- 9
- Pages
- 1050-1063
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1855231
- OpenAlex
- W2113634596
- Cited by
- 895
- References
- 68
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 18 · 2023: 35 · 2022: 21 · 2021: 35 · 2020: 39 · 2019: 37 · 2018: 44 · 2017: 65 · 2016: 55 · 2015: 65 · 2014: 98 · 2013: 77 · 2012: 70
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Agency for Science, Technology and Research
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- polycomb repressive complex 2, DZNep, EZH2, SUZ12, EED, histone H3 lysine 27 methylation, gene silencing, apoptosis, breast cancer, atrogin-1, chromatin remodeling, cancer therapy
- MeSH terms
- Adenosine, Base Sequence, Breast Neoplasms, Enzyme Inhibitors, Female, Histones, Humans, Methylation, Promoter Regions, Genetic, Repressor Proteins, RNA Polymerase II, Apoptosis, RNA Interference, RNA, Small Interfering, Chromatin Assembly and Disassembly, Adenosylhomocysteinase, Epigenesis, Genetic, Cell Line, Tumor, Chromatin Immunoprecipitation, Polycomb-Group Proteins
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