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Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma I

ABSTRACT: Epigenetic drugs exert a wide range of immune-related effects, but have strong drug-specific heterogeneity in immunomodulation, thus hampering selection of the most promising agent for innovative cancer immunotherapy approaches. Here we identified immune-related signatures induced by four classes of epigenetic drugs in melanoma cells to define the most active agent and to understand its biological activity in -vitro, in a pre-clinical model and in clinical samples. Gene modulation, induced by inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), bromodomain and extraterminal domain proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126), was assessed in human melanoma cell lines. All drugs modulated genes belonging to 20 families. Guadecitabine, followed by givinostat, was the most active drug and upregulated >160 immune-related genes characterized by low expression and high methylation. JQ1 and OTX-015 showed predominant inhibitory effects, GSK126 was the least active. A dominant immunomodulatory effect of guadecitabine and JQ1 was observed in combinatorial treatments. This experiment deals with the characterization of gene expression in untreated human melanoma cell lines used throughout the project.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189628 | GEO | 2022/11/23

REPOSITORIES: GEO

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Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma II

Project description:Epigenetic drugs exert a wide range of immune-related effects, but have strong drug-specific heterogeneity in immunomodulation, thus hampering selection of the most promising agent for innovative cancer immunotherapy approaches. Here we identified immune-related signatures induced by four classes of epigenetic drugs in melanoma cells to define the most active agent and to understand its biological activity in -vitro, in a pre-clinical model and in clinical samples. Gene modulation, induced by inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), bromodomain and extraterminal domain proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126), was assessed in human melanoma cell lines. All drugs modulated genes belonging to 20 families. Guadecitabine, followed by givinostat, was the most active drug and upregulated >160 immune-related genes characterized by low expression and high methylation. JQ1 and OTX-015 showed predominant inhibitory effects, GSK126 was the least active. A dominant immunomodulatory effect of guadecitabine and JQ1 was observed in combinatorial treatments. This experiment deals with the characterization of gene modulation by epigenetic drugs (guadecitabine, givinostat, JQ1, GSK-126) and by the unrelated drug Abemaciclib in two melanoma cells lines CST30 and VRG100

2022-11-23 | GSE189629 | GEO

Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma IV

2022-11-23 | GSE189631 | GEO

Landscape of immune-related signatures induced by targeting of epigenetic regulators in melanoma III

Project description:Epigenetic drugs exert a wide range of immune-related effects, but have strong drug-specific heterogeneity in immunomodulation, thus hampering selection of the most promising agent for innovative cancer immunotherapy approaches. Here we identified immune-related signatures induced by four classes of epigenetic drugs in melanoma cells to define the most active agent and to understand its biological activity in -vitro, in a pre-clinical model and in clinical samples. Gene modulation, induced by inhibitors of DNA methyltransferases (guadecitabine), histone deacetylases (givinostat), bromodomain and extraterminal domain proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126), was assessed in human melanoma cell lines. All drugs modulated genes belonging to 20 families. Guadecitabine, followed by givinostat, was the most active drug and upregulated >160 immune-related genes characterized by low expression and high methylation. JQ1 and OTX-015 showed predominant inhibitory effects, GSK126 was the least active. A dominant immunomodulatory effect of guadecitabine and JQ1 was observed in combinatorial treatments. This experiment deals with the characterization of gene expression in tumor nodules removed from immunodeficient mice treated or not with guadecitabine (as described in Covre A et al. Seminars in Oncology 2015;42:506-513) after s.c. tranplant of human melanoma cells from two cell lines 313 and 195 (cell lines described in Coral S et al. J. Cell Physiol 2006;207:58-66).

2022-11-23 | GSE189630 | GEO

Transcriptome sequencing wide functional analysis of human hepatocellular carcinoma in response to BRD4 inhibition

Project description:We investigated that differentially expressed genes (DEG) targeted by BET inhibitors, JQ1 and OTX-015 in HCC cells using RNA sequencing. These DEGs are involved in HCC cells migration, of which SMARCA4 inhibition is effective in suppressing HCC cell migration.

2021-06-09 | GSE158552 | GEO

RNA-seq of NK-92 cell line upon BET inhibitor treatment (OTX-015)

Project description:Identification of the mechanisms through which BET inhibitor (OTX-015) stimulates natural killer (NK) activation. RNA-seq was performed comparing vehicle- (DMSO) to OTX-015-treated NK-92 cell line.

2024-01-26 | E-MTAB-12853 | biostudies-arrayexpress

Transcriptome profiling of HCC1937 vector and wtBRCA1 cell lines which were treated with OTX-015

Project description:Purpose: To compare the transcriptomes of HCC1937 vector and wtBRCA1 cells which were treated with OTX-015. Methods: HCC1937 vector and wtBRCA1 cells were treated with 5 micromolar OTX-015 for 24 hours. Total RNA was extracted and processed with NEBNext Ultra Directional RNA Library Prep Kit for cDNA library preparation. The data are in duplicate and raw data were generated by Illumina 2500 sequencer. The Fastq format data were then processed with Tophat for genome mapping. After getting the bam files, they were further analyzed with cuffdiff for gene expression of different groups. Results: From the transcriotome profiling and analysis, we got gene expression data of DMSO control group and OTX-015 treatment group for the HCC1937 BRCA1 isogenic cell lines. Conclusion: The gene expression data revealed the transcriptome variation by OTX-015 treatment.

2019-01-30 | GSE109809 | GEO

ChIPSeq data from melanoma cancer cell line CHL-1 after Bromodomain and extra terminal (Bet) domain inhibitor treatment

Project description:Bromodomain and extra terminal domain (BET) inhibition reduces occupancy of BET-family proteins at promoter and enhancer sites finally leading to genome wide changes in gene transcription. We used ChIPSeq profiling to investigate genome wide changes in promoter and enhancer occupancy induced by BET inhibitors BAY 1238097 and OTX-015, respectively.

2017-09-30 | GSE95585 | GEO

BET Protein Inhibitor JQ1 Induces Cell Cycle Arrest in Mesenchymal Stem Cells

Project description:Efficacy and safety of anticancer drugs are traditionally studied using cancer cell lines and animal models. Recently, a potential anticancer agent, JQ1, an inhibitor of bromodomain and extra terminal (BET) protein, has been shown to promote apoptosis of cancerous cells by arresting them in G1 phase of the cell cycle. However, the effect of JQ1 on normal cells is poorly understood. In this study, we investigated the safety of JQ1 by using human umbilical cord mesenchymal stem cells (MSCs) as an in vitro model system. Our results indicated that JQ1 induced cell cycle arrest in G1 phase of MSCs, but did not promote apoptosis. Microarray analysis of MSCs treated with JQ1 indicated that it down-regulated genes involved not only in cell cycle regulation but also DNA replication, mitosis, and cell division. Although many studies have suggested the potential of JQ1 as an anticancer agent, our findings suggest that it caused a deleterious effect on normal cells and may not be safe for anticancer therapy. Human umbilical cord derived MSCs were cultured in vitro and treated with either 100 nM or 500 nM JQ1 for 24 hrs. Gene expression of treated cells was compared to untreated cultured cells.

2016-02-12 | E-GEOD-70577 | biostudies-arrayexpress

Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling the responses of T-cells, myeloid derived suppressor cells and NK cells

Project description:The combination of PD-1 and CTLA-4 blockade has determined an improved overall survival (OS) rate for malignant melanoma at 3 years of 58% as compared to ipilimumab alone. Immune checkpoint blockers (ICB) limit the tumor’s immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICB are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437). We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor’s and the host’s responses under different treatments by flow cytometry, immunohistochemistry (MANTRA), gene methylation and scRNA sequencing. Guadecitabine in combination with ICBs significantly reduced tumor growth compared to ICB and Guadecitabine treatment. The demethylating drug led to a general DNA-demethylation and transcriptional modification of gene expression. In particular, Guadecitabine greatly enhanced the efficacy of combined ICBs by increasing effector memory CD8+ T cells, inducing effector NK cells in the spleen and reducing tumor infiltrating regulatory T cells and MDSC cells, in the TME. These results indicate Guadecitabine as a promising epigenetic drug to be added to ICB therapy.

2023-04-25 | GSE220698 | GEO

Dysregulated lipid metabolism blunts the sensitivity of B16F10 melanoma cells to EZH2 inhibitor

Project description:The sensitivity has been the key issue for EZH2 inhibitor in cancer therapy. Although it has been approved by Food and Drug Administration (FDA) in 2020, the relative narrow scope still limits its clinical application. In this study, we utilized B16F10 melanoma cell line which is resistant to EZH2 inhibitor GSK126 to an extent to investigate the underlying mechanism. We found that although the proliferative phenotype didn't show any difference upon treatment with GSK126 at 10 μM, the transcriptome and metabolome changed profoundly. Gene set enrichment analysis and metabolites pathway enrichment analysis revealed that GSK126 induced broad shifts in glucose, amino acids and lipid metabolism. Lipid synthesis were strengthened with elevated abundance of unsaturated fatty acids. We also found attenuated tricarboxylic acid cycle metabolism, and decreased amino acids levels. The liver lipid accumulation and the increased blood triglycerides level after GSK126 treatment were further confirmed in a mouse model. Indeed, the combination of GSK126 and lipolysis agent fenofibrate significantly attenuated the proliferation of B16F10 and increased the sensitivity to GSK126. Therefore, the dysregulated lipid metabolism blunts the sensitivity of B16F10 to GSK126. This study uncovered the iceberg under the sea and identified the Achilles heel of EZH2 inhibitor, so that it provides the novel strategy for further combination therapy.

2022-02-23 | GSE163078 | GEO

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