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Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas.

TitlePrecision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas.
Publication TypeJournal Article
Year of Publication2019
AuthorsLue JK, Prabhu SA, Liu Y, Gonzalez Y, Verma A, Mundi PS, Abshiru NA, Camarillo JM, Mehta S, Chen EI, Qiao C, Nandakumar R, Cremers S, Kelleher NL, Elemento O, Amengual JE
JournalClin Cancer Res
Date Published2019 Apr 12
ISSN1078-0432
Abstract

PURPOSE: Both gain-of-function EZH2 mutations and inactivating histone acetyltransferases mutations, such as CREBBP and EP300, have been implicated in the pathogenesis of germinal center (GC) derived lymphomas. We hypothesized that direct inhibition of EZH2 and HDAC would be synergistic in GC-derived lymphomas.

EXPERIMENTAL DESIGN: Lymphoma cell lines (n=21) were exposed to GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor. Synergy was assessed by Excess over Bliss. Western blot, mass spectrometry and co-immunopreciptiation were performed. A SU-DHL-10 xenograft model was utilized to validate findings. Pre-treatment RNA-sequencing of cell lines was performed. MetaVIPER analysis was used to infer protein activity.

RESULTS: Exposure to GSK126 and romidepsin demonstrated potent synergy in lymphoma cell lines with EZH2 dysregulation. Combination of romidepsin with other EZH2 inhibitors also demonstrated synergy suggesting a class effect of EZH2 inhibition with romidepsin. Dual inhibition of EZH2 and HDAC led to modulation of acetylation and methylation of H3K27. The synergistic effects of the combination was due to disruption of the PRC2 complex secondary to acetylation of RbAP 46/48. A common basal gene signature was shared among synergistic lymphoma cell lines and were characterized by upregulation in chromatin remodeling genes and transcriptional regulators. This finding was supported by metaVIPER analysis which also revealed that HDAC 1/2 and DNMT were associated with EZH2 activation.

CONCLUSIONS: Inhibition of EZH2 and HDAC is synergistic and leads to the dissociation of PRC2 complex. Our findings support the clinical translation of the combination of EZH2 and HDAC inhibition in EZH2 dysregulated lymphomas.

DOI10.1158/1078-0432.CCR-18-3989
Alternate JournalClin. Cancer Res.
PubMed ID30979734
Grant ListP30 CA013696 / CA / NCI NIH HHS / United States
P41 GM108569 / GM / NIGMS NIH HHS / United States