Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 6

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

  • Text
  • PDF
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

×

Figure 2

Cell adhesion confers drug resistance to MM cells by blocking drug-induced H3K27 hypermethylation in vitro.

Options: View larger image (or click on image) Download as PowerPoint
Cell adhesion confers drug resistance to MM cells by blocking drug-induc...
(A) RPMI8226 and KMS12-BM cells were cultured in the absence or presence of either ADM (left panel) or 4-OHCY (right panel) in a cell-culture insert with (+) or without (–) direct adhesion to UBE6T-7 cells. After 72 hours of culture, cell proliferation was assessed by the MTT reduction assay and expressed as a percentage of the values of corresponding untreated cells. *P < 0.05 between adhesion (–) and (+) at the same drug concentration determined by 1-way ANOVA with the Student-Newman-Keuls multiple comparisons test (n = 3). (B) Nuclear extracts were prepared from RPMI8226 cells cultured in the presence of 0.4 μM ADM for 48 hours and subjected to immunoblotting. We used recombinant histones H3 and H4 chemically modified at corresponding sites (Active Motif) as positive controls (p.c.). See Supplemental Figure 10 for antibody validation. (C) Whole cell lysates were prepared after 48 hours of culture described in A and subjected to immunoblotting. The signal intensities of each band were quantified, normalized to those of the corresponding histone H3, and shown as relative values setting untreated controls at 1.0. (D) Relative intensities of adhesion (+)/(–) at doses of 0.4 μM ADM and 20 μM 4-OHCY, respectively, in panel C are shown. *P <0.05 against the value of histone H3 calculated by 1-way ANOVA with the Student-Newman-Keuls multiple comparisons test (n = 3).

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

Sign up for email alerts

Posted by 10 X users
On 1 Facebook pages
Mentioned in 1 Google+ posts
72 readers on Mendeley
See more details