Related Experiment Video

Updated: Mar 30, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

909

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

Jiro Kikuchi, Daisuke Koyama, Taeko Wada

    The Journal of Clinical Investigation
    |October 31, 2015
    PubMed

    Insights

    Epigenetic alterations in histone methylation contribute to chemotherapy resistance. This study reveals how cell adhesion promotes drug resistance in multiple myeloma by inhibiting histone H3-lysine 27 (H3K27) methylation, suggesting new therapeutic targets.

    Area of Science:

    • Epigenetics
    • Cancer Biology
    • Molecular Oncology

    Background:

    • Histone methylation alterations are implicated in cancer chemotherapy resistance.
    • Cell adhesion-mediated drug resistance (CAM-DR) is a significant challenge in multiple myeloma treatment.
    • Understanding epigenetic mechanisms is crucial for advancing cancer therapies.

    Purpose of the Study:

    • To investigate the role of histone H3-lysine 27 (H3K27) epigenetic modifications in multiple myeloma drug resistance.
    • To elucidate the mechanisms by which cell adhesion influences drug resistance in multiple myeloma.
    • To identify potential therapeutic strategies targeting epigenetic pathways for overcoming chemotherapy resistance.

    Main Methods:

    • Utilized a coculture system to model stroma cell adhesion-dependent drug resistance.
    • Assessed drug-induced H3K27 hypermethylation and its association with CAM-DR.
    • Investigated the role of EZH2 phosphorylation at serine 21 in regulating H3K27 methylation.
    • Examined the impact of IGF-1R/PI3K/AKT pathway inhibition on CAM-DR, EZH2 activity, and H3K27 methylation in vitro and in vivo.

    Main Results:

    • Abrogation of drug-induced H3K27 hypermethylation correlated with CAM-DR.
    • Cell adhesion inactivated EZH2 via phosphorylation, sustaining antiapoptotic gene expression (IGF1, BCL2, HIF1A).
    • Inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation.

    Conclusions:

    • Identified a novel epigenetic mechanism underlying CAM-DR in multiple myeloma involving H3K27 methylation.
    • Suggests that targeting EZH2 phosphorylation with kinase inhibitors could be a viable strategy for combination chemotherapy.
    • This approach may enhance therapeutic efficacy and overcome drug resistance in refractory multiple myeloma.

    More Related Videos

    Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype14:51

    Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

    Published on: June 17, 2022

    3.7K
    In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells10:26

    In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells

    Published on: January 20, 2019

    13.3K

    Related Concept Videos

    Treatment Resistant Cancers02:56

    Treatment Resistant Cancers

    Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
    3.9K
    Abnormal Proliferation02:23

    Abnormal Proliferation

    Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
    5.4K
    Targeted Cancer Therapies02:57

    Targeted Cancer Therapies

    The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
    There are several types of targeted therapies against...
    9.1K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
    The mTOR pathway or the...
    5.1K
    mTOR Signaling and Cancer Progression03:03

    mTOR Signaling and Cancer Progression

    No description available
    1.7K
    Combination Therapies and Personalized Medicine02:50

    Combination Therapies and Personalized Medicine

    Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
    The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
    6.3K