A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma
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 f...
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doaj-102657295ae543ceae01381242f3b9782021-02-14T12:04:54ZengNature Publishing GroupCell Death and Disease2041-48892021-02-0112211610.1038/s41419-021-03447-8A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myelomaPatrick Nylund0Alba Atienza Párraga1Jakob Haglöf2Elke De Bruyne3Eline Menu4Berta Garrido-Zabala5Anqi Ma6Jian Jin7Fredrik Öberg8Karin Vanderkerken9Antonia Kalushkova10Helena Jernberg-Wiklund11Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityDepartment of Medicinal Chemistry, Analytical Pharmaceutical Chemistry, Uppsala UniversityDepartment of Haematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB)Department of Haematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB)Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount SinaiScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityDepartment of Haematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB)Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityScience for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala UniversityAbstract 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.https://doi.org/10.1038/s41419-021-03447-8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma Cell Death and Disease |
author_facet |
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 |
author_sort |
Patrick Nylund |
title |
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_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_sort |
distinct metabolic response characterizes sensitivity to ezh2 inhibition in multiple myeloma |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-02-01 |
description |
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. |
url |
https://doi.org/10.1038/s41419-021-03447-8 |
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