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

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

doi:10.1038/s41419-021-03447-8

Cited by 13 publications

(17 citation statements)

References 70 publications

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“…After incubation in the dark for 10 min at room temperature, flow cytometry was used for detection. All these procedures were performed based on the protocols of the TACS Annexin V-FITC Apoptosis Kit (R&D Systems, Gaithersburg, USA) [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Long non-coding RNA OIP5-AS1 regulates smoke-related chronic obstructive pulmonary disease via targeting micro RNA -410-3p/IL-13

et al. 2021

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This investigation aimed to assess the levels of serum OIP5-AS1 and micro RNA-410-3p (miR-410-3p) in patients with chronic obstructive pulmonary disease (COPD) and their potential molecular mechanism. The levels of OIP5-AS1 and miR-410-3p as well as mRNA levels of IL-13 were measured. Pearson variable linear test was applied to analyze the correlations between forced expiratory volume in 1 second (FEV1) and OIP5-AS1. The receiver operating characteristic curve was used to predict the predictive possibility of OIP5-AS1. The viable cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry was used to detect the cell apoptosis. An enzyme-linked immunosorbent assay was performed to indicate the inflammatory situation of 16HBE cells. Luciferase activity assay was conducted to examine the relationships between OIP5-AS1 and miR-410-3p together with miR-410-3p and IL-13. Augmented levels of OIP5-AS1, declined levels of miR-410-3p, and enhanced expression of IL-13 were unveiled. The expression of OIP5-AS1 and miR-410-3p was related to the ratio of FEV1 respectively. OIP5-AS1 might serve as a diagnostic biomarker. Interference of OIP5-AS1 restored the abnormal cell viability, apoptosis, and inflammation in cigarette smoke extract (CSE)-stimulated 16HBE cells by regulating miR-410-3p and IL-13. OIP5-AS1 appeared to be a biomarker for distinguishing COPD patients from smokers. OIP5-AS1/miR-410-3p/IL-13 exerted function on the cell viability, apoptosis, and inflammation in CSE-steered cell models.

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Section: Methodsmentioning

confidence: 99%

Long non-coding RNA OIP5-AS1 regulates smoke-related chronic obstructive pulmonary disease via targeting micro RNA -410-3p/IL-13

et al. 2021

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“…Inhibition of EZH2 in MM leads to the downregulation of a c-MYC signature, the upregulation of cell cycle control genes including the CDK inhibitors CDKN1A/ p21 and CDKN2B/p15 leading to cell cycle arrest and apoptosis [1,98]. New evidence shows that in MM cell lines that the sensitivity to EZH2 inhibitor correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling [99].…”

Section: Prc2/ezh2 In Multiple Myelomamentioning

confidence: 99%

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer

Ghamlouch

Boyle

Blaney

et al. 2021

J Exp Clin Cancer Res

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Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.

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“…The link between methionine metabolism and drug response was recently demonstrated by us in MM [366]. In this study, we utilised cellular metabolic profiling to determine the response to an epigenetic-targeted intervention.…”

Section: Epigenetics Teams Up With the Methionine Cyclementioning

confidence: 99%

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

et al. 2021

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Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.

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

Cited by 13 publications

References 70 publications

Long non-coding RNA OIP5-AS1 regulates smoke-related chronic obstructive pulmonary disease via targeting micro RNA -410-3p/IL-13

Long non-coding RNA OIP5-AS1 regulates smoke-related chronic obstructive pulmonary disease via targeting micro RNA -410-3p/IL-13

Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer

One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

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