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Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma
Jiro Kikuchi, … , Bjarne Bogen, Yusuke Furukawa
Jiro Kikuchi, … , Bjarne Bogen, Yusuke Furukawa
Published October 26, 2015
Citation Information: J Clin Invest. 2015;125(12):4375-4390. https://doi.org/10.1172/JCI80325.
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Research Article Oncology Article has an altmetric score of 6

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

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Abstract

Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3–lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion–mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion–dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug–induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index.

Authors

Jiro Kikuchi, Daisuke Koyama, Taeko Wada, Tohru Izumi, Peter O. Hofgaard, Bjarne Bogen, Yusuke Furukawa

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Figure 14

The IGF-1R inhibitor OSI-906 overcomes CAM-DR in a syngeneic murine MM model.

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The IGF-1R inhibitor OSI-906 overcomes CAM-DR in a syngeneic murine MM m...
(A) We injected 2 × 105 luciferase-expressing MOPC315.BM.Luc cells intravenously into BALB/c mice and treated them in 4 ways: the vehicle alone (control), 30 mg/kg CY, 30 mg/kg OSI-906 (OSI), and the combination of both agents (CY + OSI). Treatments were started 2 weeks after transplantation, defined as day 0. In vivo luciferase activity of whole body was measured by the IVIS Imaging System on day 14. Photographs of all BALB/c mice on day 14 are shown. Original magnification, ×2. (B) Quantitative data of in vivo bioluminescence imaging expressed as photon units. *P < 0.05 determined by 1-way ANOVA with the Tukey’s multiple comparison test (n = 3). (C) BM sections were obtained from the femurs corresponding to the circled regions in A and subjected to H&E and immunofluorescent chemical (IFC) staining. Immunofluorescent chemical specimens were stained with anti–phospho-EZH2 at S21 (p-EZH2), followed by staining with Alexa Fluor 488–conjugated anti-rabbit IgG (green), and PE-conjugated anti-mouse CD138 (red) antibodies. Nuclei were counterstained with DAPI (blue). Only merged images are shown. Scale bars: 200 μm (upper panels); 50 μm (middle and lower panels). Data shown are representative results of 3 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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