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EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas
Yasuyuki Otsuka1, Momoko Nishikori1, Hiroshi Arima1
1Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
Abstract:
Loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. CD58 loss is known to occur due to both genetic and non-genetic causes; therefore, we hypothesized that restoring CD58 expression in lymphoma cells may be an effective treatment approach. To explore the potential for restoring CD58 expression, we first screened 11 B-cell lymphoma lines and found that 3 had decreased CD58 expression. Among these, CD58 was genetically damaged in two lines but not in the third line. Using the cell line with downregulated CD58 without a genetic abnormality, we performed epigenetic library screening and found that two EZH2 inhibitors, EPZ6438 and GSK126, specifically enhanced CD58 expression. By examining the effect of three EZH2 inhibitors with different selectivity profiles in different B-cell lines, EZH2 inhibition was shown to have a common activity in upregulating CD58 expression. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance interferon-γ production of T and NK cells against lymphoma cells. H3K27 was shown to be highly trimethylated in the CD58 promoter region, and EZH2 inhibition induced its demethylation and activated transcription of the CD58 gene. These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment.
Insights
Restoring CD58 expression in lymphoma cells via EZH2 inhibitors can enhance anti-tumor immunity. This approach targets epigenetic silencing, offering a new strategy for lymphoma treatment.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Loss of CD58 is a key mechanism for tumor immune evasion in lymphoid malignancies.
- CD58 downregulation can result from genetic or non-genetic factors, necessitating exploration of therapeutic restoration.
Purpose of the Study:
- To investigate the potential of restoring CD58 expression in lymphoma cells as a treatment strategy.
- To identify epigenetic mechanisms and therapeutic targets for CD58 re-expression.
Main Methods:
- Screening of B-cell lymphoma lines to identify CD58 downregulation.
- Epigenetic library screening using EZH2 inhibitors (EPZ6438, GSK126) on a lymphoma cell line with epigenetically silenced CD58.
- Analysis of EZH2 inhibitor effects on CD58 expression and T/NK cell activity.
- Chromatin immunoprecipitation to assess H3K27 trimethylation at the CD58 promoter.
Main Results:
- Three out of eleven B-cell lymphoma lines showed decreased CD58 expression.
- EZH2 inhibitors EPZ6438 and GSK126 specifically upregulated CD58 expression in a cell line with epigenetic silencing.
- EZH2 inhibition broadly enhanced CD58 expression across different B-cell lines and boosted T and NK cell-mediated anti-lymphoma activity.
- EZH2 inhibition led to demethylation of H3K27 at the CD58 promoter, activating its transcription.
Conclusions:
- EZH2 plays a role in the epigenetic silencing of CD58 in lymphoma, contributing to immune escape.
- EZH2 inhibitors can restore epigenetically suppressed CD58 expression, enhancing anti-tumor immune responses.
- These findings support the combination of EZH2 inhibitors with immunotherapy for lymphoma treatment.
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