Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma.

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461430
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: Kikuchi Jiro 自治医科大学, 医学部, 准教授 (60371035)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 造血器腫瘍 / 薬剤耐性 / エピジェネティクス

Outline of Final Research Achievements

Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. We identified histone H3-lysine 27 (H3K27) as a critical residue for epigenetic modification associated with cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted anticancer drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to the sustained expression of IGF1, BCL2 and HIF1A. Pharmacological and genetic inhibition of the IGF-1R/PI3K/Akt was able to reverse CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Our finding is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy to increase the therapeutic index.

Free Research Field

医歯薬学