Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma.
| Project/Area Number |
26461430
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
Kikuchi Jiro 自治医科大学, 医学部, 准教授 (60371035)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 造血器腫瘍 / 薬剤耐性 / エピジェネティクス |
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| 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.
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Report
(4 results)
Research Products
(31 results)
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[Journal Article] Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome-Positive Lymphoid Leukemia.2016
Author(s)
Nemoto A, Saida S, Kato I, Kikuchi J, Furukawa Y, Maeda Y, Akahane K, Honna-Oshiro H, Goi K, Kagami K, Kimura S, Sato Y, Okabe S, Niwa A, Watanabe K, Nakahata T, Heike T, Sugita K, Inukai T.
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Journal Title
Mol Cancer Ther.
Volume: 15
Issue: 1
Pages: 94-105
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergic effects with pyrimidine analogues in lymphoid malignancies.2014
Author(s)
Hiraoka N, Kikuchi J, Koyama D, Uesawa M, Akutsu M, Wada T, Abe M, Mori S, Nakamura Y, Kano Y, and Furukawa Y.
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Journal Title
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Anti-leukemic activity of Carfilzomib against B-cell precursor ALL2016
Author(s)
Kazuya Takahashi, Takeshi Inukai, Meixian Huang, Itaru Kuroda, Kinuko Hirose, Atsushi Waatanabe, Shinpei Somazu, Kumiko Goi, Kaiko Kagami, Masako Abe, Kanji Sugita, Chihiro Tomoyasu, Mio Yano, Toshihiko Imamura, Hajime Hosoi, Jiro Kikuchi, Yusuke Furukawa
Organizer
第７８回日本血液学会学術集会
Place of Presentation
パシフィコ横浜(神奈川県横浜市)
Year and Date
2016-10-13
Related Report
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