Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition

Amatangelo, Michael; Garipov, Azat; Li, Hua; Conejo-Garcia, José R.; Speicher, David W.; Zhang, Rugang

doi:10.4161/cc.25163

Cited by 75 publications

(65 citation statements)

References 27 publications

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“…A potential limitation of our proliferation results could be the experimental assay system used. Three-dimensional cultures approximating physiologic conditions have been proposed for EZH2 inhibitors to fully cover potential effects of epigenetic reprogramming (21,37). Nevertheless, our gene expression profiling after loss of global H3K27me3 is different for cell lines having comparable genetic alterations.…”

Section: Discussionmentioning

confidence: 77%

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Hernando

Gelato

Lesche

et al. 2016

Molecular Cancer Therapeutics

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Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 77%

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Hernando

Gelato

Lesche

et al. 2016

Molecular Cancer Therapeutics

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“…Cells were cultured in growth factor reduce matrigel as described previously (19). Briefly, 40 μL of matrigel was plated on Falcon culture slides.…”

Section: Methodsmentioning

confidence: 99%

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Fatkhutdinov

Sproesser

Krepler

et al. 2016

Molecular Cancer Research

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The majority of melanoma patients harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression free survival of only 6–7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate limiting for de novo dNTP synthesis, as a poor prognostic factor in mutant BRAF melanoma patients. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell cycle arrest.

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“…This morphology assay to assess malignancy or to define a therapeutic that blocks growth and/or invasion in 3D is also adaptable to high-throughput screening. In addition, ovarian tumor cells in 3D culture on basement membrane matrix have recently been found to be more sensitive to methyltransferase inhibition demonstrating the important role of the tumor microenvironment [57]. Thus, the basement membrane matrix mimics the in vivo microenvironment of tumor cells and affects not only the morphology of the cells but also their molecular responses.…”

Section: Tumor Cells In 3d Culturementioning

confidence: 97%

Matrigel: From discovery and ECM mimicry to assays and models for cancer research

Benton

Arnaoutova

George

et al. 2014

Advanced Drug Delivery Reviews

339

278

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Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition

Cited by 75 publications

References 27 publications

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes

Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma

Matrigel: From discovery and ECM mimicry to assays and models for cancer research

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