A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma

Patrick Nylund,Antonia Kalushkova,Alba Atienza Párraga,Jakob Haglöf,Berta Garrido-Zabala,Elke De Bruyne,Helena Jernberg-Wiklund,Fredrik Öberg,Eline Menu,Karin Vanderkerken,Jian Jin,Anqi Ma

doi:10.1038/s41419-021-03447-8

Abstract

Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.

Highlights

Multiple myeloma (MM) is a genetically and clinically heterogeneous haematological disease, characterized by a monoclonal expansion of malignant plasmablasts/plasma cells in the bone marrow[1,2,3]
Combining liquid chromatography-mass spectrometry (LC-MS), chromatin immunoprecipitation (ChIP), gene and miRNA expression profiling, we identified distinct alterations in the methionine cycling pathways in cell lines that responded to enhancer of zeste homologue 2 (EZH2) inhibition (EZH2i), which were absent in non-responsive cell lines
We found that methionine adenosyltransferase 2A (MAT2A), AHCY, MTR and MTAP were increased in monoclonal gammopathy of undetermined significance (MGUS) and smouldering myeloma (SM) as compared to normal plasma cells[23] (Supplementary Fig. 5a, c, f and h)

Summary

Introduction

Multiple myeloma (MM) is a genetically and clinically heterogeneous haematological disease, characterized by a monoclonal expansion of malignant plasmablasts/plasma cells in the bone marrow[1,2,3]. A complex mutational landscape, high heterogeneity and a genome-wide epigenetic reconfiguration may contribute to the underlying causes of drug resistance and relapse[4,5,6]. We have previously demonstrated that the gene silencing profile of MM cells is reminiscent of the one of embryonic fibroblasts, where the Polycomb repressive complex 2 (PRC2) is highly active[7]. Metabolic profiles are altered upon drug treatment, panels of metabolites have been used as biomarkers for drug response[14,15]. The association between the metabolome and the epigenome is, complex. It is well known that chromatin regulators require metabolite intermediates as cofactors and that different metabolic pathways associated with tumorigenesis are epigenetically regulated[16]. The impact of epigenetic targeting on the cellular metabolome is largely unexplored

Methods

Results

Conclusion