Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription

Yang, Liping; Chen, Shengchuan; Zhao, Qun; Pan, Chaohu; Peng, Lei; Yu, Han; Li, Lili; Ruan, Jiayin; Xia, Jingyan; Yang, Heng; Xu, Feng; Cheng, Genhong

doi:10.1016/j.celrep.2022.110302

Cited by 25 publications

(20 citation statements)

References 50 publications

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“…In MCC cells treated with domatinostat that did not undergo apoptosis, we observed upregulation of molecules involved in antigen presentation, including the antigen processing-associated transporter (TAP) and proteasome subunits that generate peptides for MHC class I loading, which are normally regulated by type I IFNs. Because of the essential function of HDACs in modulating immune responses, the influence of HDACi on the regulation of type I IFNs has already been addressed in several studies, showing downregulation in some studies and upregulation in others (Salvi et al 2010;Yang et al 2022;Li et al 2016). The latter may be explained by the fact that the expression of IFNs in cancer cells can be either constitutive or inducible, depending on the cell type and the specific molecular mechanisms involved (Cheon et al 2023).…”

Section: Discussionmentioning

confidence: 99%

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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Background Class I selective histone deacetylase inhibitors (HDACi) have been previously demonstrated to not only increase major histocompatibility complex class I surface expression in Merkel cell carcinoma (MCC) cells by restoring the antigen processing and presentation machinery, but also exert anti-tumoral effect by inducing apoptosis. Both phenomena could be due to induction of type I interferons (IFN), as has been described for HDACi. However, the mechanism of IFN induction under HDACi is not fully understood because the expression of IFNs is regulated by both activating and inhibitory signaling pathways. Our own preliminary observations suggest that this may be caused by suppression of HES1. Methods The effect of the class I selective HDACi domatinostat and IFNα on cell viability and the apoptosis of MCPyV-positive (WaGa, MKL-1) and -negative (UM-MCC 34) MCC cell lines, as well as, primary fibroblasts were assessed by colorimetric methods or measuring mitochondrial membrane potential and intracellular caspase-3/7, respectively. Next, the impact of domatinostat on IFNA and HES1 mRNA expression was measured by RT-qPCR; intracellular IFNα production was detected by flow cytometry. To confirm that the expression of IFNα induced by HDACi was due to the suppression of HES1, it was silenced by RNA interference and then mRNA expression of IFNA and IFN-stimulated genes was assessed. Results Our studies show that the previously reported reduction in viability of MCC cell lines after inhibition of HDAC by domatinostat is accompanied by an increase in IFNα expression, both of mRNA and at the protein level. We confirmed that treatment of MCC cells with external IFNα inhibited their proliferation and induced apoptosis. Re-analysis of existing single-cell RNA sequencing data indicated that induction of IFNα by domatinostat occurs through repression of HES1, a transcriptional inhibitor of IFNA; this was confirmed by RT-qPCR. Finally, siRNA-mediated silencing of HES1 in the MCC cell line WaGa not only increased mRNA expression of IFNA and IFN-stimulated genes but also decreased cell viability. Conclusion Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.

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Section: Discussionmentioning

confidence: 99%

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Srinivas

Song

Lei

et al. 2023

J Cancer Res Clin Oncol

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“…HDAC inhibitors are utilized for cancer treatment due to their anticancer functions, such as induction of cell cycle arrest, antiangiogenesis, apoptosis induction, suppression of cell migration and invasion, and immune modulation 29–31 . In addition, HDAC inhibitors suppressed the type‐1 IFN response related to host virus defense 23–25 . HDAC inhibition assists multiple processes of oncolytic virotherapy, such as enhancing virus entry, replication, propagation, and spread; decreasing antivirus response; promoting apoptosis; and induction of tumor antigen expression 27,28 .…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Nakatake,

Kurosaki,

Nakamura

2023

Cancer Science

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Oncolytic viruses have two anticancer functions: direct oncolysis and elicitation of antitumor immunity. We previously developed a novel fusogenic oncolytic vaccinia virus (FUVAC) from a non‐fusogenic vaccinia virus (VV) and, by remodeling the tumor immune microenvironment, we demonstrated that FUVAC induced stronger oncolysis and antitumor immune responses compared with non‐fusogenic VV. These functions depend strongly on cell–cell fusion induction. However, FUVAC tends to have decreased fusion activity in cells with low virus replication efficacy. Therefore, another combination strategy was required to increase cell–cell fusion in these cells. Histone deacetylase (HDAC) inhibitors suppress the host virus defense response and promote viral replication. Therefore, in this study, we selected an HDAC inhibitor, trichostatin A (TSA), as the combination agent for FUVAC to enhance its fusion‐based antitumor potential. TSA was added prior to FUVAC treatment of murine tumor B16‐F10 and CT26 cells. TSA increased the replication of both FUVAC and parental non‐fusogenic VV. Moreover, TSA enhanced cell–cell fusion and FUVAC cytotoxicity in these tumor cells in a dose‐dependent manner. Transcriptome analysis revealed that TSA‐treated tumors showed altered expression of cellular component‐related genes, which may affect fusion tolerance. In a bilateral tumor‐bearing mouse model, combination treatment of TSA and FUVAC significantly prolonged mouse survival compared with either treatment alone or in combination with non‐fusogenic VV. Our findings demonstrate that TSA is a potent enhancer of cell–cell fusion efficacy of FUVAC.

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“…This suggests that Hdac3 normally represses the AIM2 inflammasome through deacetylation of STAT1 (Zhang et al, 2020). Similarly, in macrophages Hdac3 interacts with the transcription factor FOXK1 to regulate expression of STAT1 (Yang et al, 2022). Future work will be needed to evaluate these alternative protein targets of Hdac3 in microglial gene regulation and function.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 regulates microglial function through histone deacetylation

Meleady

Towriss

Bacarac

et al. 2022

Preprint

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Background As the primary innate immune cells of the brain microglia respond to damage and disease through pro-inflammatory release of cytokines and neuroinflammatory molecules. Histone acetylation is an activating transcriptional mark that regulates gene expression, which is altered in states of disease. Inhibition of histone deacetylase 3 (Hdac3) has been utilized in pre-clinical models of disease to dampen inflammation, but the molecular mechanisms underlying Hdac3's regulation of inflammatory gene expression in microglia is not well understood. Methods Functional changes in immortalized microglia were characterized using a Hdac3 specific inhibitor RGFP966 in response to an immune challenge lipopolysaccharide (LPS). Flow cytometry and cleavage under tags & release using nucleases (CUT & RUN) were used to investigate global and promoter-specific histone acetylation changes, resulting in altered gene expression. Results Hdac3 inhibition enhanced neuroprotective functions of microglia in response to LPS through reduced nitric oxide release and increased baseline phagocytosis. Inhibition of Hdac3 enhanced histone acetylation globally and at specific gene loci, resulting in the release of gene repression at baseline and enhanced responses to LPS. Conclusion The findings suggest Hdac3 serves as a negative regulator of microglial gene expression, and that inhibition of Hdac3 facilitates the microglial response to inflammation and its subsequent resolution. Together, this work provides new mechanistic insights into therapeutic applications of Hdac3 inhibition which mediate reduced neuroinflammatory insults through microglial response.

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Histone deacetylase 3 contributes to the antiviral innate immunity of macrophages by interacting with FOXK1 to regulate STAT1/2 transcription

Cited by 25 publications

References 50 publications

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

The HDAC inhibitor domatinostat induces type I interferon α in Merkel cell carcinoma by HES1 repression

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Histone deacetylase 3 regulates microglial function through histone deacetylation

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