Effects of HDACi on Immunological Functions

Winkler, René; Kosan, Christian

doi:10.1007/978-1-4939-6527-4_7

Cited by 3 publications

(4 citation statements)

References 13 publications

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“…Dijke et al (51) demonstrated that B cells could regulate cellular immunity, contribute to the genesis of tolerance and induce accommodation. Several studies have reported that HDAC inhibitors could regulate the B cell function in various immunological disorders (27,52,53). For instance, HDAC inhibitors could be used as immunomodulatory agents in order to regulate B cell responses to allogeneic transplantation (54).…”

Section: Discussionmentioning

confidence: 99%

“…Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl from histones, and serve an important role in immune cells by altering chromatin structure and regulating specific transcription factors (26). HDAC inhibitors have been used as immunomodulatory agents in B-cell-mediated autoimmune diseases, B cell lymphomas and multiple myelomas can be treated by modulating B cell function (27). HDAC-8 inhibitors affected the regulation of reversion-inducing-cysteine-rich protein with kazal motifs and altered the structure of chromosomes associated with tumorigenesis in leukemia (28).…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation

Zhou

Mei

et al. 2021

Mol Med Rep

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Heart transplantation is widely used for the treatment of several heart diseases. Regulatory B cells (Breg cells) serve a critical role in immune tolerance. However, the role of Breg cells in immune tolerance in the context of allogeneic heart transplantation remains poorly understood. The present study aimed to explore the effect of histone deacetylase (HDAC) inhibitor trichostatin A (TSA)-regulated Breg on the regulation of immune tolerance in heart transplantation. By constructing anallogeneic heart transplantation mouse model, and performing flow cytometry, reverse transcription-quantitative PCR, western blotting and carboxyfluorescein succinimidyl esterstaining assays, TSA-regulated Breg cells and their effects on immune tolerance in heart transplantation were evaluated. The results demonstrated that TSA increased the frequency of CD19 + CD5 + CD1d high Breg cells both in vitro and in vivo. Moreover, TSA treatment increased the frequency of IL-10 and TGF-β-producing CD19 + CD5 + CD1d high Breg cells, and IL-10 and TGF-β levels in vitro and in vivo. TSA administration significantly prolonged the survival rate in a heart transplant experiment model. In addition, the IL-10 inhibitor ammonium trichloro(dioxoethylene-o,o')tellurate partially reduced the survival rate and the percentages of CD19 + CD5 + CD1d high Breg cells in mice receiving heart allografts. In contrast, anti-CD20 treatment significantly decreased the survival rate in these mice. Collectively, the present findings suggested that TSA may induce immune tolerance following heart transplantation by regulating CD19 + CD5 + CD1d high Breg cells. These results provide a theoretical basis for the prevention of immunological rejection in cardiac transplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation

Zhou

Mei

et al. 2021

Mol Med Rep

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“…All cell lines were tested regularly for Mycoplasma infection. Isolation of primary B-cells was performed as previously described [ 56 ]. Primary B-cells were grown in RPMI 1640 with 10% FCS, 50 µM β-mercaptoethanol, 10 mM HEPES and 0.5% gentamicin.…”

Section: Methodsmentioning

confidence: 99%

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

et al. 2022

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Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

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“…All cell lines were tested regularly for Mycoplasma infection. Isolation of primary B-cells was performed as previously described (56). Primary B-cells were grown in RPMI 1640 with 10 % FCS, 50 μM β-mercaptoethanol, 10 mM HEPES and 0.5 % gentamicin.…”

Section: Methodsmentioning

confidence: 99%

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Winkler

Mägdefrau

Kleemann

et al. 2021

Preprint

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Overexpression of oncogenic MYC is the hallmark of many lymphomas and is related to a poor prognosis. Although MYC is a potential cancer driver, therapeutic targeting is still challenging. Here, we report that histone deacetylase 6 (HDAC6) inhibition using the novel inhibitor Marbostat-100 (M-100) specifically alters protein-protein interactions in MYC-dependent cancer cells and targets MYC for proteasomal degradation. Subsequently, massive apoptosis is induced in MYC-overexpressing B-cell lymphoma cells after M-100 treatment. Besides, the application of M-100 prevents lymphoma formation in Eμ-Myc transgenic mice and efficiently slows down tumor growth in already manifested lymphomas. Moreover, M-100 exclusively targets MYC-dependent tumor cells with little or no side effects on non-tumor cells and tissues. HDAC6 inhibition results in pleiotropic cellular effects, such as hyperacetylation of Tubulin. We propose a mechanism where the heat-shock protein DNAJA3 associates with acetylated Tubulin to control MYC turnover in malignant cells. Our data show a new mechanism how HDAC6 inhibition targets oncogenic MYC in lymphomas and demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

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Effects of HDACi on Immunological Functions

Cited by 3 publications

References 13 publications

Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation

Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

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Effects of HDACi on Immunological Functions

Cited by 3 publications

References 13 publications

Protective effect of trichostatin A on CD19+CD5+CD1dhigh regulatory B cells in heart transplantation

Protective effect of trichostatin A on CD19+CD5+CD1dhigh regulatory B cells in heart transplantation

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

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Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation

Protective effect of trichostatin A on CD19⁺CD5⁺CD1d^high regulatory B cells in heart transplantation