4.8 Article

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 12, Pages 4375-4390

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI80325

Keywords

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Funding

  1. High-Tech Research Center Project for Private Universities: a Matching Fund Subsidy from MEXT
  2. Japan Society for the Promotion of Science [25118721, 25461434, 26461438]
  3. Japan Leukemia Research Fund
  4. Yasuda Memorial Cancer Foundation
  5. Takeda Science Foundation
  6. Kano Foundation Research grant
  7. Award in Aki's Memory
  8. International Myeloma Foundation Japan
  9. Grants-in-Aid for Scientific Research [26461438, 25461434, 25118721] Funding Source: KAKEN

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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/Iymphoma 2 (BCL2), and hypoxia inducible factor 1, alpha subunit (H/F1A). Pharmacological and genetic inhibition of the IGF-1R/P13K/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.

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