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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number167
Number of pages16
JournalCell & Death Disease
Volume12
Issue number2
DOIs
Publication statusPublished - 12 Feb 2021

Keywords

  • Multiple myeloma
  • heterogeneous haematological disease
  • epigenetic silencer EZH2
  • markers
  • treatment
  • cancer

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