Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell-mediated Killing by Regulating Immune-related Genes

Abstract

Abstract. Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading cause of death of cancer patients in the world (1). Although a lot of progress has been made in the clinical management of HCC, its prognosis still remains poor owing to high chances of metastasis and recurrence, leading to low overall survival (2). Treatment options for advanced HCC are extremely limited owing to the shortage of effective therapeutic agents. Currently, sorafanib is the only approved therapeutic agent for advanced HCC (3), so there is an urgent need for novel therapeutic drugs for this disease.Recently, epigenetic modulation of gene transcription through acetylation and deacetylation has been reported to play a role in the pathogenesis of advanced HCC (4-6). Specifically, histone deacetylases (HDAC)1-3 are upregulated in primary human HCC and the enhanced HDACs levels play a critical role in malignant growth and immune escape (7). Importantly, the deacetylation process is reversible and can be targeted by new drugs such as HDAC inhibitors (8, 9). Thus, the biology of HDACs in HCC makes the use of HDAC inhibitors to treat HCC an attractive option (9-11). HDAC inhibitors have been shown to have efficacy as anti-cancer agents in numerous phase I/II studies (http://www.clinicaltrials.gov), conducted in many different types of cancer (12,13).Trichostatin A (TSA) was originally discovered as an antifungal drug, but was later found to be a potent non-selective 349

Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells

“…These two cell types are important innate cell components in various immune-related diseases and antimicrobial defense systems (Fig. 4) and are a component of antitumoral and antiviral immunity 17–19 . These findings suggest that MAIT cells and NK cells are effector components equipped with differential signaling or sensing systems to broaden a range of host defenses.…”

A short-chain fatty acid, propionate, enhances the cytotoxic effect of cisplatin by modulating GPR41 signaling pathways in HepG2 cells

“…Epigenetic modulation of gene transcription through acetylation and deacetylation of histones plays an important role in the pathogenesis of HCC [ 19 ]. Expression of HDAC1-5 and 8 is upregulated in human HCC and enhanced expression of HDACs plays a critical role in malignant growth and immune escape [ 19 , 20 ]. In contrast to genetic alterations, such epigenetic changes are reversible, and therefore are good therapeutic targets [ 21 ].…”

The role of natural killer cells in hepatocellular carcinoma development and treatment: A narrative review

“…The antifungal HDACI trichostatin A indirectly kills HCC cells by increasing NK cell cytotoxicity of HCC cells via transcriptional modulation of important genes such as ULBP1 and RAET1G. Directly, it can increase apoptosis of HCC cells [124]. Lomofungin is an FDA approved antifungal,that decreases ADAM17 activity which then decreases sMICA in a dose dependent manner [125].…”

“…Inhibition of RET, c-KIT, c-RAF, TIE-2, PDGFR, VEGFR1–3, FGFR-1, p38 MAP kinase and BRAF2. Inhibition of STAT3 signaling pathway leading to the enhancement of NK cell cytolytic activity and apoptosis of HCC cellsPhase 2GermanyNCT03644511[118], [119], [120]HDACIsSuberoylanilide hydroxamic acid (SAHA)Suppression of the miRNAs targeting MICA/B in order to lower the threshold of MICA/B expressionInduction of MICA expression causing enhancement of NK cell-mediated HCC cell eradicationPhase 1USANCT01075113[35], [38], [121]Sodium valproateIncreasing cytotoxic activity of NK cells[59]HDACI MS-275Upregulate expression of MICA, MICB and HSP70 leading to enhanced NK cytotoxicity in HepG2 lines[122]DisulfiramEnhancement of antitumor activity of Natural Killer cells by suppressing sMICA production with enzymatic inhibition of ADAM10[123]AntimicrobialsTrichostatin A (an antifungal HDACI)Indirectly kills HCC cells by increasing NK cell cytotoxicity of HCC cells via transcriptional modulation of important genes such as ULBP1 and RAET1GDirectly kills HCC cells by increasing apoptosis of HCC cells[124]Lomofungin (antifungal)Decreasing ADAM17 activity which then decreases sMICA in a dose dependent manner[125]Anisomycin (antibiotic)Modulation of a broad range of genes such as lymphocyte-associated antigen-3, MHC-1, CD58, and ICAM4 in order to improve formation of immunological synapses between Natural killer and Hepatocellular carcinoma cells[126]Novel Treatment optionsTT-1 (synthetic novel peptide analog of Melittin, an anti-arthritic, anti-microbial, anti-inflammatory and anti-tumor drug)Combination of TT-1 with IFN-α enhances NK cells activity against HCC cells by promoting NKG2D and MICA interaction[127]Mel-P15 (Melittin analog)Direct stimulation of NK cytotoxicityIncreasing secretion of IL-2, TNF-α and IFN-γ[128]GastrodinEnhancement of cytotoxicity of Natural killer cells and CD8+ T lymphocytes…”