ArticleJournal of biomolecular screening2015
Quantification of histone H3 Lys27 trimethylation (H3K27me3) by high-throughput microscopy enables cellular large-scale screening for small-molecule EZH2 inhibitors.
Article in Journal of biomolecular screening, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 26 citations in OpenAlex.
- A miniaturized mode-of-action profiling platform enables high throughput characterization of the molecular and cellular dynamics of EZH2 inhibition.Scientific reports · 2024Article
- Screening for Small-Molecule Inhibitors of Histone Methyltransferases.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications.International journal of molecular sciences · 2021Review
- Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome.Nature communications · 2020Article
- Uncovering epigenetic landscape: a new path for biomarkers identification and drug development.Molecular biology reports · 2020Review
- Improving drug discovery using image-based multiparametric analysis of the epigenetic landscape.eLife · 2019Article
- Orchestration of H3K27 methylation: mechanisms and therapeutic implication.Cellular and molecular life sciences : CMLS · 2018Review
- A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro.International journal of molecular sciences · 2017Review
- Epigenetic assays for chemical biology and drug discovery.Clinical epigenetics · 2017Review
- The Histone Methyltransferase Enzyme Enhancer of Zeste Homolog 2 Protects against Podocyte Oxidative Stress and Renal Injury in Diabetes.Journal of the American Society of Nephrology : JASN · 2016Article
- Cell-based assays to support the profiling of small molecules with histone methyltransferase and demethylase modulatory activity.Drug discovery today. Technologies · 2015Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
EZH2 inhibition can decrease global histone H3 lysine 27 trimethylation (H3K27me3) and thereby reactivates silenced tumor suppressor genes. Inhibition of EZH2 is regarded as an option for therapeutic cancer intervention. To identify novel small-molecule (SMOL) inhibitors of EZH2 in drug discovery, trustworthy cellular assays amenable for phenotypic high-throughput screening (HTS) are crucial. We describe a reliable approach that quantifies changes in global levels of histone modification marks using high-content analysis (HCA). The approach was validated in different cell lines by using small interfering RNA and SMOL inhibitors. By automation and miniaturization from a 384-well to 1536-well plate, we demonstrated its utility in conducting phenotypic HTS campaigns and assessing structure-activity relationships (SAR). This assay enables screening of SMOL EZH2 inhibitors and can advance the mechanistic understanding of H3K27me3 suppression, which is crucial with regard to epigenetic therapy. We observed that a decrease in global H3K27me3, induced by EZH2 inhibition, comprises two distinct mechanisms: (1) inhibition of de novo DNA methylation and (II) inhibition of dynamic, replication-independent H3K27me3 turnover. This report describes an HCA assay for primary HTS to identify, profile, and optimize cellular active SMOL inhibitors targeting histone methyltransferases, which could benefit epigenetic drug discovery.
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