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A transcriptomic dataset used to derive biomarkers of chemically induced histone deacetylase inhibition (HDACi) in human TK6 cells.

ABSTRACT: Transcriptomic biomarkers facilitate mode of action analysis of toxicants by detecting specific patterns of gene expression perturbations. We identified an 81-gene transcriptomic biomarker of histone deacetylase inhibitors (HDACi) using whole transcriptome data sets of TK6 human lymphoblastoid cells generated by Templated Oligo-Sequencing (TempO-Seq) after 4 h of exposure to 20 reference compounds (10 HDACi and 10 non-HDACi) [1]. The biomarker, named TGx-HDACi, was derived using the nearest shrunken centroid (NSC) method and can distinguish HDACi from non-HDACi compounds based on the expression pattern across the 81 genes. The classification capability of TGx-HDACi was evaluated by NSC probability analysis of 11 external validation compounds (4 HDACi and 7 non-HDACi) with a probability cut-off of 90%. Thus far, TGx-HDACi has demonstrated 100% accuracy in classifying the reference and validation compounds as HDACi or non-HDACi. Of the 81 TGx-HDACi genes, 19 genes are part of the S1500+ gene panel containing 2753 genes, developed for toxicological assessments [2]. Herein, we assessed the classification performance of the biomarker with this reduced gene set to determine if TGx-HDACi can be applied to analyze S1500+ gene expression profiles. The 20 reference compounds and 11 validation compounds were correctly classified as HDACi or non-HDACi by the NSC probability analysis, principal component analysis, and hierarchical clustering based on the expression of the 19 genes, demonstrating 100% accuracy.

SUBMITTER: Cho E

PROVIDER: S-EPMC8138725 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Development of a transcriptomic biomarker to detect histone deacetylase inhibitors (HDACi) in TK6 cells

Project description:Transcriptomic signatures, or biomarkers, of toxicity can facilitate rapid mechanistic analysis of chemicals using high-content transcriptomic data and identification of potential hazards to human health. We developed an 81-gene transcriptomic biomarker, named TGx-HDACi, to detect histone deacetylase inhibitors (HDACi) in TK6 human lymphoblastoid cells after 4 hours of chemical exposure. This work leveraged an established transcriptomic biomarker of DNA damage, TGx-DDI, which was developed by Heng Hong Li et al. (2015); TGx-DDI contains 63 genes and can distinguish between DNA damage-inducing (DDI) and non-DDI agents after 4 hours of exposure in TK6 cells. TGx-HDACi was derived from Templated Oligo-Sequencing (TempO-Seq) whole transcriptome gene expression profiles of 20 reference compounds, consisting of 10 HDACi and 10 non-HDACi compounds. Fourteen of the TGx-HDACi reference compounds are also part of the 28-compound reference set for TGx-DDI. The nearest shrunken centroid (NSC) method was applied to the gene expression profiles and 81 genes were identified that accurately identified HDACi compounds in the NSC probability analysis. The classification performance of TGx-HDACi was validated using an additional set of 11 test compounds (4 HDACi and 7 non-HDACi). Thus far, TGx-HDACi has demonstrated 100% accuracy. The availability of TGx-HDACi increases the diversity of tools that can facilitate mode of action analysis of toxicants using gene expression profiling.

2021-04-14 | GSE164478 | GEO

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Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi.

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Development of a transcriptomic biomarker to detect histone deacetylase inhibitors (HDACi) in TK6 cells

Project description:Development of a transcriptomic biomarker to detect histone deacetylase inhibitors (HDACi) in TK6 cells

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Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency.

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In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi).

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| S-EPMC7370100 | biostudies-literature

Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations.

Project description:PURPOSE:Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL. METHODS:The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels of intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations were evaluated. RESULTS:Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction. CONCLUSIONS:A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin.

| S-EPMC5837827 | biostudies-literature

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