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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Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

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 13

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

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The IGF-1R inhibitor OSI-906 overcomes CAM-DR in a xenograft murine MM m...
(A) We subcutaneously inoculated 5 × 106 luciferase-expressing RPMI8226-Luc cells and 5 × 106 UBE6T-7 cells separately in the right and left thighs, respectively (separate) or a mixture of the 2 cell types in the right thigh (mixed) of NOD/SCID mice. Mice were treated in 4 ways: vehicle alone (control), 30 mg/kg CY, 30 mg/kg OSI-906 (OSI), and a combination of both agents (CY + OSI). Treatments were started when inoculated tumors were measurable, defined as day 0. On day 14, in vivo luciferase activity of whole body was measured by d-luciferin injection and the IVIS Imaging System. Representative photographs of NOD/SCID mice on day 0 and day 14 are shown. Original magnification, ×2. Inoculated tumors on day 0 are indicated in circled regions. (B) Quantitative data of in vivo bioluminescence imaging on day 14 expressed as photon units (photons/s). *P < 0.05 determined by 1-way ANOVA with the Tukey’s multiple comparison test (n = 3).