Rôle de EZH2 comme biomarqueur dans le traitement personnalisé du myélome multiple

Herviou, Laurie; Cavalli, Giacomo; Moreaux, Jérôme

doi:10.1016/j.bulcan.2018.06.003

Cited by 5 publications

(5 citation statements)

References 85 publications

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“…The enhancer of Zeste Homologue 2 (EZH2) is the catalytic subunit of the polycomb repressor protein complex 2 (PRC2). EZH2 can mediate the 3 methylation states of H3K27, however, the most investigated action of EZH2 is gene silencing through trimethylation of H3K27 (H3K27me3) (79, 80). EZH2 mediated trimethylation of H3K27 recruits canonical PRC1 and other corepressive factors to the DNA by serving as a docking site.…”

Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

“…Importantly, several studies identified polycomb group genes, including EZH2, as crucial factors mediating stem cell pluripotency and self-renewal (79, 84, 85). EZH2 overexpression is described in various solid cancers and hematological malignancies, including lung, breast, and pancreatic cancer and diffuse large B cell lymphoma, and is often linked to a more aggressive phenotype and unfavorable prognosis (83, 86).…”

Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

“…Different EZH2i, such as GSK-926, GSK-343, EPZ-005687, EPZ-6438 (tazemetostat), EI1 and CPI-169, are currently under clinical investigation in solid tumors and in lymphomas, both as single agents and in combination strategies. One of the most investigated inhibitors is EPZ-6438, which showed promising results in clinical trials in lymphoma patients with minimal toxicity problems (79, 106). In MM, disappointing results of a clinical trial investigating the use of GSK2816126 as a single agent so far halted the further development of this agent.…”

Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

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The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

et al. 2018

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Multiple myeloma (MM) is a clonal plasma cell malignancy that develops primarily in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, growth, and drug resistance. MM cells furthermore reshape the BM to their own needs by affecting the different BM stromal cell types resulting in angiogenesis, bone destruction, and immune suppression. Despite recent advances in treatment modalities, MM remains most often incurable due to the development of drug resistance to all standard of care agents. This underscores the unmet need for these heavily treated relapsed/refractory patients. Disruptions in epigenetic regulation are a well-known hallmark of cancer cells, contributing to both cancer onset and progression. In MM, sequencing and gene expression profiling studies have also identified numerous epigenetic defects, including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and genetic defects, copy number variations and/or abnormal expression patterns of various chromatin modifying enzymes. Importantly, these so-called epimutations contribute to genomic instability, disease progression, and a worse outcome. Moreover, the frequency of mutations observed in genes encoding for histone methyltransferases and DNA methylation modifiers increases following treatment, indicating a role in the emergence of drug resistance. In support of this, accumulating evidence also suggest a role for the epigenetic machinery in MM cell plasticity, driving the differentiation of the malignant cells to a less mature and drug resistant state. This review discusses the current state of knowledge on the role of epigenetics in MM, with a focus on deregulated histone methylation modifiers and the impact on MM cell plasticity and drug resistance. We also provide insight into the potential of epigenetic modulating agents to enhance clinical drug responses and avoid disease relapse.

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Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

Section: Histone Methylation Enzymes and Multiple Myelomamentioning

confidence: 99%

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The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

et al. 2018

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“…Previous researches have reported the overexpression of EZH2 without mutation in MM [22][23][24]. Additionally, despite the heterogeneity observed in MM, bone marrow cells isolated from patients with MM or MM cell lines displayed constitutive activation and up-regulation of STAT3, while no mutations were observed [25,26].…”

Section: Discussionmentioning

confidence: 86%

EZH2 Promotes Multiple Myeloma Progression via STAT3 Pathway Activation

Wang,

Tian,

Huang

et al. 2024

Discovery Medicine

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Background: Multiple myeloma (MM) is a malignant disorder of plasma cells in the bone marrow. MM causes the clonal proliferation of terminally differentiated plasma cells and the accumulation of monoclonal plasma cells. The enhancer of zeste homolog 2 (EZH2) has been proven to play a significant role in disease development and could act on the signal transducers and activators of the transcription 3 (STAT3) signaling pathway. This pathway contributes to the pathogenesis and maintenance of malignancies. This study aimed to explore the effect of EZH2 on MM progression and the role of the STAT3 pathway in this process. The goal was to increase knowledge and provide further insights about the pathogenesis of MM and identify novel targets for potential therapies. Methods: The abnormal expression of EZH2 in MM cell lines was tested through real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analysis. Based on the MM cell line H929, transfection was used to modify EZH2 expression, followed by the subsequent evaluation of induced alteration in STAT3 activation. The STAT3 phosphorylation activator colivelin and inhibitor stattic were used for promoting and inhibiting the STAT3 activation, respectively. Colony-forming assay, transwell migration assay, and flow cytometry were used to explore cell proliferation, cell migration, and cell apoptosis, respectively. Results: Both the EZH2 mRNA and protein were over-expressed in multiple MM cell lines including H929 (p < 0.001), U266 (p < 0.01), RPMI-8226 (p < 0.01) and MM.1S (p < 0.001). Increased EZH2 promoted cell proliferation (p < 0.001) and migration (p < 0.001) and simultaneously inhibited cell apoptosis (p < 0.001), which could be reversed by inhibited STAT3 activation (p < 0.001). In contrast, promoted STAT3 activation increased cell proliferation (p < 0.001) and migration (p < 0.001), while simultaneously inhibiting cell apoptosis (p < 0.001), despite decreased EZH2 expression. Conclusions: The effect of EZH2 and STAT3 pathways on MM regulation was revealed and verified. EZH2 promoted the progression of MM cells by activating the STAT3 pathway. The EZH2 and STAT3 pathways could be potential targets for effective MM treatment.

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“…EZH2 is a protein-coding gene that encodes a histone methyltransferase that serves as the catalytic subunit of PRC2. It has been reported that mutations in EZH2 are associated with a number of different types of cancer, such as gastric cancer and hematological malignancies, and high EZH2 expression is associated with metastatic disease in pediatric soft tissue sarcomas (37). Richter et al (38) demonstrated that EZH2 promotes tumorigenesis by shaping the oncogenicity and stem cell phenotype in ES pathology (38).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of Ewing's sarcoma: Seeking key candidate genes and pathways

Zhang

et al. 2019

Oncol Lett

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Ewing's sarcoma (ES) is the second most common bone tumor among children and adolescents worldwide. However, the genes and signaling pathways involved in ES tumorigenesis and progression remain unclear. The present study used two gene-expression profile datasets (GSE17674 and GSE31215) to elucidate key potential candidate genes and pathways in ES. Differentially expressed genes (DEGs) were identified and a functional enrichment analysis was performed. A protein-protein interaction (PPI) network was constructed, and the most significant module in the PPI network was selected from the Search Tool for the Retrieval of Interacting Genes/Proteins database. A total of 278 genes were identified by comparing the tumor samples with non-cancerous samples; these included 272 upregulated and 6 downregulated genes. The pathway analysis demonstrated significant enrichment in the positive regulation of transcription in the DEGs coding for RNA polymerase II promoter, plasma membrane and chromatin binding pathways in cancer in general. There were 269 nodes and 292 edges in the PPI network. Finally, MYC, IGF1, OAS1, EZH2 and ISG15 were identified as the hub genes according to the degree levels. The survival analysis revealed that EZH2 is associated with a poor prognosis in patients with ES. In conclusion, the DEGs, associated pathways and hub genes identified in the present study help elucidate the underlying molecular mechanisms of ES carcinogenesis and progression, and provide potential molecular targets and biomarkers for ES.

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Rôle de EZH2 comme biomarqueur dans le traitement personnalisé du myélome multiple

Cited by 5 publications

References 85 publications

The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response

EZH2 Promotes Multiple Myeloma Progression via STAT3 Pathway Activation

Bioinformatics analysis of Ewing's sarcoma: Seeking key candidate genes and pathways

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