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Updated: Feb 21, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone deacetylase inhibitors downregulate CCR4 expression and decrease mogamulizumab efficacy in CCR4-positive
Akihiro Kitadate1,2, Sho Ikeda1, Fumito Abe1
1Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine.
Abstract:
Histone deacetylase inhibitors are promising agents for various T-cell lymphomas, including cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and adult T-cell lymphoma/leukemia. CCR4 is an important therapeutic target molecule because mogamulizumab, an anti-CCR4 antibody, has shown promising efficacy against various T-cell lymphomas. In this study, we examined the in vitro synergistic effects of mogamulizumab and histone deacetylase inhibitors against various T-cell lymphomas. First, we examined the expression of CCR4 mRNA and surface CCR4 in various T-cell lymphoma cell lines and found that it was downregulated upon treatment with vorinostat, a pan-histone deacetylase inhibitor. Next, we used isoform-specific histone deacetylase inhibitors and short-interfering RNA to determine the histone deacetylase isoform involved in the regulation of CCR4, and demonstrated that romidepsin, a class I selective histone deacetylase inhibitor, reduced CCR4 most efficiently. Moreover, among class I histone deacetylases, histone deacetylase 2 knockdown led to a reduction of CCR4 in lymphoma cells, suggesting that CCR4 expression is mainly regulated by histone deacetylase 2. When we examined the CCR4 expression in skin samples from primary cutaneous T-cell lymphoma, obtained from the same patients before and after vorinostat treatment, we found that CCR4 expression was greatly reduced after treatment. Finally, when we conducted an antibody-dependent cell-mediated cytotoxicity assay with mogamulizumab by using various lymphoma cells, we found that the efficacy of mogamulizumab was significantly reduced by pretreatment with vorinostat. Altogether, our results suggest that the primary use of histone deacetylase inhibitors before treatment with mogamulizumab might not be suitable to obtain synergistic effects. Moreover, these results have potential implications for optimal therapeutic sequences in various CCR4-positive T-cell lymphomas.
Insights
Histone deacetylase inhibitors reduce CCR4 expression in T-cell lymphomas, potentially impacting mogamulizumab efficacy. Pre-treatment with these inhibitors may not be optimal for synergistic effects in CCR4-positive lymphomas.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Histone deacetylase inhibitors (HDACi) show promise for T-cell lymphomas.
- CCR4 is a therapeutic target, with mogamulizumab demonstrating efficacy.
- Understanding drug interactions is crucial for optimizing T-cell lymphoma treatment.
Purpose of the Study:
- To investigate the in vitro synergistic effects of mogamulizumab and HDAC inhibitors on T-cell lymphomas.
- To determine the role of specific histone deacetylase (HDAC) isoforms in regulating CCR4 expression.
- To evaluate the impact of HDAC inhibitor pre-treatment on mogamulizumab efficacy.
Main Methods:
- Examined CCR4 mRNA and surface expression in T-cell lymphoma cell lines.
- Utilized pan-HDAC and isoform-specific HDAC inhibitors, alongside short-interfering RNA (siRNA) for knockdown studies.
- Assessed CCR4 expression in patient skin samples before and after vorinostat treatment.
- Performed antibody-dependent cell-mediated cytotoxicity (ADCC) assays with mogamulizumab.
Main Results:
- Vorinostat, a pan-HDAC inhibitor, downregulated CCR4 expression in T-cell lymphoma cell lines and patient samples.
- Romidepsin, a class I selective HDAC inhibitor, most efficiently reduced CCR4.
- HDAC2 knockdown significantly reduced CCR4 expression, indicating its primary regulatory role.
- Mogamulizumab efficacy was reduced when lymphoma cells were pre-treated with vorinostat.
Conclusions:
- HDAC2 is a key regulator of CCR4 expression in T-cell lymphomas.
- Pre-treatment with HDAC inhibitors may diminish the therapeutic efficacy of mogamulizumab.
- Optimal therapeutic sequencing of HDAC inhibitors and mogamulizumab requires careful consideration for CCR4-positive T-cell lymphomas.
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