EZH2 inhibitors sensitize myeloma cell lines to panobinostat resulting in unique combinatorial transcriptomic changes

Abstract

Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation. Pre-treatment with EZH2 inhibitors greatly enhanced the sensitivity of HMCLs to the pan-HDAC inhibitor panobinostat in nearly all cases regardless of single agent EZH2 inhibitor sensitivity. Transcriptomic profiling revealed large-scale transcriptomic alteration by EZH2 inhibition highly enriched for cancer-related pathways. Combination treatment greatly increased the scale of gene expression change with a large portion of differentially expressed genes being unique to the combination. Transcriptomic analysis demonstrated that combination treatment further perturbed oncogenic pathways and signaling nodes consistent with an antiproliferative/pro-apoptotic state. We conclude that combined inhibition of HDAC and EZH2 inhibitors is a promising therapeutic strategy to broadly target the epigenetic landscape of aggressive MM.

Epigenetic Aberrations in Multiple Myeloma

“…Overall, targeting the PHF19-PRC2-EZH2 complex could represent a novel therapeutic strategy for MM treatment. Indeed, EPZ-643 and GSK-126, known as EZH2 inhibitors, were shown to sensitize MM cells to HDAC inhibitor panobinostat, favoring MM cell apoptosis and reducing MM cell survival [ 55 ]. Similarly, recent studies have demonstrated how PRC2 inhibitors were able to inhibit MM tumorigenicity [ 54 , 55 ].…”

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

“…These mechanisms may involve microRNA silencing of TAZ, as has been shown in other cancers, 61 or other epigenetic modifiers. In several studies, including some genome-wide screens, TAZ was found to be upregulated in response to silencing the histone demethylase JMJD1a 62 or treatment with epigenetic inhibitors such as BTZ, 63 enhancer of zeste homolog 2 (EZH2) inhibitors, 64 the panHDAC inhibitor Pano, 65 and the BET inhibitor JQ1. 66 We show that the TAZ promoter is specifically methylated ( Figure 2C) and that globally inhibiting DNMTs increased TAZ expression in HMCLs ( Figure 5A-D).…”

EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

“…Synergistic or re-sensitizing effects between EZH2 inhibitors and traditional cytotoxic anti-cancer drugs have been seen [155,156]. In view of the abundantly present epigenetic abnormalities of H3K27 tri-methylation and histone acetylation, a couple of studies have combined EZH2 inhibitors with different HDAC inhibitors for the treatment in MM [157,158] and B cell lymphoma cells [54,123,159,160], and favorable therapeutic coordination were observed. Dual-targeting of MYC and EZH2 has been employed to disrupt MYC-EZH2 oncogenic axis in aggressive B cell lymphoma cells [51].…”