Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J 2017 Mar 31;7(3):e549
Date
04/01/2017Pubmed ID
28362441Pubmed Central ID
PMC5380911DOI
10.1038/bcj.2017.27Scopus ID
2-s2.0-85024387963 (requires institutional sign-in at Scopus site) 77 CitationsAbstract
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.
Author List
Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI, Mirabella F, Jones JR, Kaiser MF, Walker BA, Jackson GH, Clarke PA, Bergsagel PL, Workman P, Chesi M, Morgan GJ, Davies FEAuthor
Test W. User test user title in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ApoptosisBiomarkers
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Cell Survival
Enhancer of Zeste Homolog 2 Protein
Epigenesis, Genetic
Gene Expression
Gene Expression Profiling
Histones
Humans
Kaplan-Meier Estimate
Multiple Myeloma
Phenotype
Prognosis
Proportional Hazards Models
RNA, Messenger