ArticleNeoplasia (New York, N.Y.)2012
Valproic acid upregulates NKG2D ligand expression through an ERK-dependent mechanism and potentially enhances NK cell-mediated lysis of myeloma.
Article in Neoplasia (New York, N.Y.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Review
- Unraveling the implications of ULBP1 expression from pan-cancer to head and neck squamous cell carcinoma.Scientific reports · 2026Article
- Targeting the MICA/B-NKG2D axis in cancer: from molecular structure to immunotherapeutic strategies-a narrative review.Translational cancer research · 2026Review
- HVJ-E links Apolipoprotein d to antitumor effects.Journal for immunotherapy of cancer · 2025Article
- Tinostamustine (EDO-S101), an Alkylating Deacetylase Inhibitor, Enhances the Efficacy of Daratumumab in Multiple Myeloma by Upregulation of CD38 and NKG2D Ligands.International journal of molecular sciences · 2024Article
- Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma.Frontiers in immunology · 2024Article
- Natural killer cells affect the natural course, drug resistance, and prognosis of multiple myeloma.Frontiers in cell and developmental biology · 2024Review
- Panobinostat enhances NK cell cytotoxicity in soft tissue sarcoma.Clinical and experimental immunology · 2022Article
- Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies.Exploration of immunology · 2022Article
- MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated.Frontiers in cell and developmental biology · 2022Article
- Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis.Frontiers in genetics · 2022Article
- Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression.Cancers · 2021Review
- Leveraging NKG2D Ligands in Immuno-Oncology.Frontiers in immunology · 2021Review
- Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway.Oncotarget · 2020Article
- Inhibition of Histone Deacetylase (HDAC) Enhances Checkpoint Blockade Efficacy by Rendering Bladder Cancer Cells Visible for T Cell-Mediated Destruction.Frontiers in oncology · 2020Article
- Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy.International journal of molecular sciences · 2019Review
- Review
- Cancer Exosomes as Conveyors of Stress-Induced Molecules: New Players in the Modulation of NK Cell Response.International journal of molecular sciences · 2019Review
- Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells.Frontiers in immunology · 2019Article
- Small-Molecule Targets in Tumor Immunotherapy.Natural products and bioprospecting · 2018Review
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5 authors.
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Abstract
Modulation of the antitumor immune response through the engagement of NKG2D receptors with their ligands (L) on targets represents a promising therapeutic approach against cancer. In this study, we tested the effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on the expression of NKG2D ligands in myeloma cells. We demonstrated that VPA was able to upregulate both protein and mRNA expression of major histocompatibility complex class I-related chain (MIC) A/B and UL16-binding protein (ULBP) 2 without any significant effect on the expression of ULBP1, ULBP3, and ULBP4 or induction of other natural killer (NK) cell ligands, such as NKp30-L, NKp44-L, and NKp46-L in myeloma cells. A (51)Cr release assay and degranulation assay indicated that the induction of MICA/B and ULBP2 augmented NK cell-mediated lysis of myeloma cells, which was abolished by the addition of a blocking NKG2D antibody. Activation of constitutively phosphorylated extracellular signal-regulated kinase (ERK) by VPA is essential for the up-regulation of MICA/B and ULBP2 expressions. Inhibition of ERK using ERK inhibitor PD98059 decreased both MICA/B and ULBP2 expressions and NK cell cytotoxicity. Furthermore, overexpression of constitutively active ERK in ARK resulted in increased MICA/B and ULBP2 expressions and enhanced NK cell lysis. These data indicate that increased sensitivity of VPA-treated myeloma cells to NK cell lysis is caused by higher NKG2D ligand expression, resulting from more active ERK signaling pathway. Our results provide evidence that targeting ERK signaling pathway may be an additional mechanism supporting the antimyeloma activity of HDAC inhibitors and suggest its possible immunotherapeutic value for myeloma treatment.
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