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

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 respon...

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Autores principales: Nylund, Patrick, Atienza Párraga, Alba, Haglöf, Jakob, De Bruyne, Elke, Menu, Eline, Garrido-Zabala, Berta, Ma, Anqi, Jin, Jian, Öberg, Fredrik, Vanderkerken, Karin, Kalushkova, Antonia, Jernberg-Wiklund, Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881125/
https://www.ncbi.nlm.nih.gov/pubmed/33579905
http://dx.doi.org/10.1038/s41419-021-03447-8
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author Nylund, Patrick
Atienza Párraga, Alba
Haglöf, Jakob
De Bruyne, Elke
Menu, Eline
Garrido-Zabala, Berta
Ma, Anqi
Jin, Jian
Öberg, Fredrik
Vanderkerken, Karin
Kalushkova, Antonia
Jernberg-Wiklund, Helena
author_facet Nylund, Patrick
Atienza Párraga, Alba
Haglöf, Jakob
De Bruyne, Elke
Menu, Eline
Garrido-Zabala, Berta
Ma, Anqi
Jin, Jian
Öberg, Fredrik
Vanderkerken, Karin
Kalushkova, Antonia
Jernberg-Wiklund, Helena
author_sort Nylund, Patrick
collection PubMed
description 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.
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spelling pubmed-78811252021-02-25 A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma Nylund, Patrick Atienza Párraga, Alba Haglöf, Jakob De Bruyne, Elke Menu, Eline Garrido-Zabala, Berta Ma, Anqi Jin, Jian Öberg, Fredrik Vanderkerken, Karin Kalushkova, Antonia Jernberg-Wiklund, Helena Cell Death Dis Article 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. Nature Publishing Group UK 2021-02-12 /pmc/articles/PMC7881125/ /pubmed/33579905 http://dx.doi.org/10.1038/s41419-021-03447-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nylund, Patrick
Atienza Párraga, Alba
Haglöf, Jakob
De Bruyne, Elke
Menu, Eline
Garrido-Zabala, Berta
Ma, Anqi
Jin, Jian
Öberg, Fredrik
Vanderkerken, Karin
Kalushkova, Antonia
Jernberg-Wiklund, Helena
A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title_full A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title_fullStr A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title_full_unstemmed A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title_short A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
title_sort distinct metabolic response characterizes sensitivity to ezh2 inhibition in multiple myeloma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881125/
https://www.ncbi.nlm.nih.gov/pubmed/33579905
http://dx.doi.org/10.1038/s41419-021-03447-8
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