Quantitative proteomic analysis of EZH2 inhibition in acute myeloid leukemia reveals the targets and pathways that precede the induction of cell death
- Author(s)
- Sandow, JJ; Infusini, G; Holik, AZ; Brumatti, G; Averink, TV; Ekert, PG; Webb, AI;
- Details
- Publication Year 2017-04-26,Volume 11,Issue #9-10,Page doi: 10.1002/prca.201700013
- Journal Title
- Proteomics Clinical Applications
- Publication Type
- Journal Article
- Abstract
- PURPOSE: Chromosomal translocation of the Mixed Lineage Leukemia (MLL) locus generates fusion proteins that drive acute myeloid leukemia (AML) resulting in atypical histone methyltransferase activity and alterations in the epigenetic regulation of gene expression. Targeting histone regulators, such as Enhancer of Zeste Homologue 2 (EZH2), has shown promise in AML. Profiling differential protein expression following inhibition of epigenetic regulators in AML may help to identify novel targets for therapeutics. EXPERIMENTAL DESIGN: Murine models of AML combined with quantitative SILAC analysis were used to identify differentially expressed proteins following inhibition of EZH2 activity using 3-Deazaneplanocin A (DZnep). Western blotting and flow cytometry were used to validate a subset of differentially expressed proteins. Gene set analysis was used to determine changes to reported EZH2 target genes. RESULTS: Our quantitative proteomic analysis and subsequent validation of protein changes identified that epigenetic therapy leads to cell death preceded by the induction of differentiation with concurrent p53 up-regulation and cell cycle arrest. Gene set analysis revealed a specific subset of EZH2 target genes that were regulated by DZnep in AML. CONCLUSIONS AND CLINICAL RELEVANCE: These discoveries highlight how this new class of drugs affects AML cell biology and cell survival, and may help identify novel targets and strategies to increase treatment efficacy. This article is protected by copyright. All rights reserved.
- Publisher
- Wiley
- Research Division(s)
- Cell Signalling And Cell Death; Stem Cells And Cancer; Systems Biology And Personalised Medicine
- PubMed ID
- 28447382
- Publisher's Version
- https://doi.org/10.1002/prca.201700013
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2017-05-02 03:01:30
Last Modified: 2018-07-09 03:42:04