HDAC Inhibition Induces CD26 Expression on Multiple Myeloma Cells via the c-Myc/Sp1-mediated Promoter Activation
Hiroko Nishida1,2, Reiko Suzuki3, Kiyora Nakajima1
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Cancer Research Communications
|January 29, 2024
Summary
Histone deacetylase inhibition (HDACi) upregulates CD26 expression on multiple myeloma cells, enhancing their sensitivity to anti-CD26 mAb therapy. This combination overcomes resistance in CD26-negative cells, improving anti-myeloma response.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- CD26 expression is heterogeneous in multiple myeloma (MM) cells, impacting therapy response.
- Decreased CD26 levels in MM cells contribute to resistance against anti-CD26 mAb therapy.
- Targeting CD26 is a strategy to improve MM treatment outcomes.
Purpose of the Study:
- To investigate the effect of histone deacetylase inhibitors (HDACi) on CD26 expression in MM cells.
- To determine if HDACi can sensitize CD26-negative MM cells to anti-CD26 mAb therapy.
- To elucidate the molecular mechanisms underlying HDACi-induced CD26 expression.
Main Methods:
- Treatment of CD26-negative MM cells with broad or class-specific HDAC inhibitors.
- Assessment of CD26 expression and dipeptidyl peptidase IV (DPP IV) activity.
- Combination therapy studies with HDACi and anti-CD26 mAb.
- Chromatin immunoprecipitation (ChIP) assays to analyze promoter interactions and histone acetylation.
- Analysis of c-Myc and Sp1 binding to the CD26 promoter.
Main Results:
- HDACi treatment induced both transcriptional and translational upregulation of CD26 expression on CD26-negative MM cells.
- Concomitant enhancement of DPP IV enzymatic activity was observed in MM cells.
- Combined HDACi and anti-CD26 mAb treatment synergistically increased the lysis of CD26-negative MM cells.
- HDACi increased histone 3 lysine 27 acetylation at the CD26 promoter.
- HDACi promoted the detachment of c-Myc from the CD26 promoter via Sp1, with increased c-Myc acetylation, leading to CD26 gene transcription.
Conclusions:
- HDACi upregulates CD26 expression on multiple myeloma cells through epigenetic modifications involving c-Myc/Sp1.
- HDACi sensitizes CD26-negative myeloma cells to anti-CD26 mAb therapy, enhancing direct and antibody-dependent cellular cytotoxicity.
- Combination therapy of HDACi and anti-CD26 mAb offers a promising strategy to overcome therapeutic resistance in multiple myeloma.
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