Molecular Regulation of MHC Class I Chain-Related Protein A Expression after HDAC-Inhibitor Treatment of Jurkat T Cells

Andresen, Lars Ole; Jensen, Hans Grinsted; Pedersen, Marianne Terndrup; Hansen, Kjeld; Skov, Søren

doi:10.4049/jimmunol.179.12.8235

Cited by 49 publications

(62 citation statements)

References 46 publications

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“…Suspension cells were cultured as previously described (29). The HEK293 Phoenix cell line was kindly provided by Dr. M. T. Petersen (Biotech Research and Innovation Centre, University of Copenhagen) and cultured in DMEM with GlutaMax (Invitrogen), 10% FBS, and 2 mmol/l streptomycin and penicillin.…”

Section: Cellsmentioning

confidence: 99%

“…Cell-surface staining was done as previously described (29), using the PEconjugated anti-human MICA/B clone 6D4, anti-human MHC class I clone W6/32 (sc-32235; Santa Cruz Biotechnology), and anti-human ICAM-1 (C170; Leinco Technologies). For intracellular staining, we used the BD Cytofix/Cytoperm kit (555028; BD Biosciences) following the manufacturer's protocol.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Transient transfections of Jurkat cells were done using an Amaxa Nucleofector kit as previously described (Lonza) (29). Standard Calcium phosphate transfection method was used for transfection of HEK293 Phoenix cells.…”

Section: Transient Transfectionsmentioning

confidence: 99%

“…Standard Calcium phosphate transfection method was used for transfection of HEK293 Phoenix cells. The pmax-GFP plasmid was provided in the Amaxa Nucleofector kit (Lonza), and the MICA promoter plasmid, p3.2k-WT-GFP, was previously described (29). Promoter activity was calculated as previously described (29).…”

Section: Transient Transfectionsmentioning

confidence: 99%

“…The pmax-GFP plasmid was provided in the Amaxa Nucleofector kit (Lonza), and the MICA promoter plasmid, p3.2k-WT-GFP, was previously described (29). Promoter activity was calculated as previously described (29). The pMyc-MICA plasmid was made by cloning the MICA coding sequence into pENTR-D-TOPO vector (Invitrogen) and then recombining this vector with pCMV-Myc using standard Gateway technology (Invitrogen).…”

Section: Transient Transfectionsmentioning

confidence: 99%

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2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation

Andresen

Skovbakke

Persson

et al. 2012

The Journal of Immunology

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NKG2D ligand surface expression is important for immune recognition of stressed and neotransformed cells. In this study, we show that surface expression of MICA/B and other NKG2D ligands is dependent on N-linked glycosylation. The inhibitor of glycolysis and N-linked glycosylation, 2-deoxy-d-glucose (2DG), potently inhibited surface expression of MICA/B after histone deacetylase inhibitor treatment; the inhibition occurred posttranscriptionally without affecting MICA promoter activity. Transient overexpression of MICA surface expression was also inhibited by 2DG. 2DG blocks N-linked glycosylation of MICA/B by a reversible mechanism that can be alleviated by addition of d-mannose; this does not, however, affect the inhibition of glycolysis. Addition of d-mannose restored MICA/B surface expression after 2DG treatment. In addition, specific pharmacological or small interfering RNA-mediated targeting of glycolytic enzymes did not affect MICA/B surface expression, strongly suggesting that N-linked glycosylation, and not glycolysis, is essential for MICA/B surface expression. Corroborating this, tunicamycin, a selective inhibitor of N-linked glycosylation, abolished MICA/B surface expression without compromising activation of MICA promoter activity. NK cell-mediated killing assay and staining with a recombinant NKG2D–Fc fusion protein showed that all functional NKG2D ligands induced by histone deacetylase inhibitor treatment were abolished by 2DG treatment and fully reconstituted by further addition of d-mannose. Our data suggest that posttranslational N-linked glycosylation is strictly required for NKG2D ligand surface expression. Cancer and infection often result in aberrant glycosylation, which could likely be involved in modulation of NKG2D ligand expression. Our data further imply that chemotherapeutic use of 2DG may restrict NKG2D ligand surface expression and inhibit secretion of immunoinhibitory soluble NKG2D ligands.

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Section: Cellsmentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

Section: Transient Transfectionsmentioning

confidence: 99%

Section: Transient Transfectionsmentioning

confidence: 99%

Section: Transient Transfectionsmentioning

confidence: 99%

See 3 more Smart Citations

2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation

Andresen

Skovbakke

Persson

et al. 2012

The Journal of Immunology

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Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma

Sasagawa,

Kumai,

Wakamatsu

et al. 2024

Cancer Innovation

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BackgroundSynovial sarcoma (SS) is an SS18‐SSX fusion gene‐driven soft tissue sarcoma with mesenchymal characteristics, associated with a poor prognosis due to frequent metastasis to a distant organ, such as the lung. Histone deacetylase (HDAC) inhibitors (HDACis) are arising as potent molecular targeted drugs, as HDACi treatment disrupts the SS oncoprotein complex, which includes HDACs, in addition to general HDACi effects. To provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells, we examined cellular responses to HDACi treatment in combination with two‐dimensional (2D) and 3D culture conditions.MethodsUsing several SS cell lines, biochemical and cell biological assays were performed with romidepsin, an HDAC1/2 selective inhibitor. SN38 was concomitantly used as an ameliorant drug with romidepsin treatment. Cytostasis, apoptosis induction, and MHC class I polypeptide‐related sequence A/B (MICA/B) induction were monitored to evaluate the drug efficacy. In addition to the conventional 2D culture condition, spheroid culture was adopted to evaluate the influence of cell‐mass microenvironment on chemoresistance.ResultsBy monitoring the cellular behavior with romidepsin and/or SN38 in SS cells, we observed that responsiveness is diverse in each cell line. In the apoptotic inducible cells, co‐treatment with SN38 enhanced cell death. In nonapoptotic inducible cells, cytostasis and MICA/B induction were observed, and SN38 improved MICA/B induction further. As a novel efficacy of SN38, we revealed TWIST1 suppression in SS cells. In the spheroid (3D) condition, romidepsin efficacy was severely restricted in TWIST1‐positive cells. We demonstrated that TWIST1 downregulation restored romidepsin efficacy even in spheroid form, and concomitant SN38 treatment along with romidepsin reproduced the reaction.ConclusionsThe current study demonstrated the benefits and concerns of using HDACi for SS treatment in 2D and 3D culture conditions and provided molecular evidence that concomitant treatment with SN38 can overcome drug resistance to HDACi by suppressing TWIST1 expression.

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Celastrol acts as a new histone deacetylase inhibitor to inhibit colorectal cancer cell growth via regulating macrophage polarity

Wang

Chen

et al. 2022

Cell Biology International

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The tumorigenesis and progression of colorectal cancer are closely related to the tumor microenvironment, especially inflammatory response. Inhibitors of histone deacetylase (HDAC) have been reported as epigenetic regulators of the immune system to treat cancer and inflammatory diseases and our results demonstrated that Celastrol could act as a new HDAC inhibitor. Considering macrophages as important members of the tumor microenvironment, we further found that Celastrol could influence the polarization of macrophages to inhibit colorectal cancer cell growth. Specially, we used the supernatant of HCT116 and SW480 cells to induce Ana-1 cells in vitro and chose the spontaneous colorectal cancer model APC min/+ mice as an animal model to validate in vivo. The results indicated that Celastrol could reverse the polarization of macrophages from M2 to M1 through impacting the colorectal tumor microenvironment both in vitro and in vivo. Furthermore, using bioinformatics analysis, we found that Celastrol might mechanistically polarize the macrophages through MAPK signaling pathway. In conclusion, our findings identified that Celastrol as a new HDAC inhibitor and suggested that Celastrol could modulate macrophage polarization, thus inhibiting colorectal cancer growth, which may provide some novel therapeutic strategies for colorectal cancer.

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Molecular Regulation of MHC Class I Chain-Related Protein A Expression after HDAC-Inhibitor Treatment of Jurkat T Cells

Cited by 49 publications

References 46 publications

2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation

2-Deoxy d-Glucose Prevents Cell Surface Expression of NKG2D Ligands through Inhibition of N-Linked Glycosylation

Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma

Celastrol acts as a new histone deacetylase inhibitor to inhibit colorectal cancer cell growth via regulating macrophage polarity

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