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Integrative Epigenetic Analysis Reveals Therapeutic Targets to the DNA Methyltransferase Inhibitor SGI-110 in Hepatocellular Carcinoma Cells [methylation]

ABSTRACT: For the AcceSssIble assay, nuclei preparation and M.SssI methyltransferase (New England BioLabs) treatment were performed. The subsequent Infinium DNA methylation assay was performed at the University of Southern California Molecular Genomics Core Facility according to the manufacturer’s specifications (Illumina).

ORGANISM(S): Homo sapiens

PROVIDER: GSE105066 | GEO | 2018/06/26

REPOSITORIES: GEO

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SGI-110: DNA Methyltransferase Inhibitor Oncolytic.

Project description:SGI-110 is a second-generation hypomethylating prodrug whose active metabolite is the well-characterized drug decitabine. This novel compound is an oligonucleotide consisting of decitabine linked through a phosphodiester bond to the endogenous nucleoside deoxyguanosine. The dinucleotide configuration provides protection from drug clearance by deamination, while maintaining at least equivalent effects on gene-specific and global hypomethylation both in vitro and in animal model systems. This agent is currently being tested in phase I and II clinical trials in humans and has been demonstrated to be safe and well tolerated as a single agent, with evidence of promising activity in heavily pretreated (including currently FDA approved hypomethylating drugs) myelodysplastic syndrome and acute myeloid leukemia patients. Ongoing trials are also open in platinum-resistant ovarian cancer and hepatocellular carcinoma.

| S-EPMC4503259 | biostudies-literature

Effects of SGI-110 on A2780 ovarian cancer xenografts

2014-10-02 | GSE55613 | GEO

Effects of SGI-110 on A2780 ovarian cancer xenografts

Project description:Genome-wide DNA methylation profiles of SGI-110-treated ovarian cancer xenografts were obtained using next generation Illumina Infinium 450k assay which includes over 450,000 GpG sites. DNA from 6 samples were hybridized to the Illumina's Infinium HumanMethylation 450 BeadChip

2014-10-02 | E-GEOD-55613 | biostudies-arrayexpress

Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin.

Project description:Promoter DNA hypermethylation is an important biomarker of hepatocellular carcinoma (HCC), supporting the potential utility of demethylating agents in this disease. Guadecitabine (SGI-110) is a second-generation hypomethylating agent formulated as a dinucleotide of decitabine and deoxyguanosine that yields longer half-life and more extended decitabine exposure than decitabine IV infusion. Here we performed preclinical evaluation of SGI-110 in HCC models to guide the design of a phase I/II clinical trial. HCC cell lines and xenograft models were used to determine the antitumor activity of SGI-110 as a single agent and in combination with oxaliplatin. Pretreatment with low doses of SGI-110 significantly synergized with oxaliplatin yielding enhanced cytotoxicity. The combination of SGI-110 and oxaliplatin was well tolerated and significantly delayed tumor growth in mice compared to oxaliplatin alone. Bromouridine-labeled RNA sequencing (Bru-seq) was employed to elucidate the effects of SGI-110 and/or oxaliplatin on genome-wide transcription. SGI-110 and the combination treatment inhibited the expression of genes involved in WNT/EGF/IGF signaling. DNMT1 and survivin were identified as novel PD markers to monitor the efficacy of the combination treatment. In conclusion, SGI-110 priming sensitizes HCC cells to oxaliplatin by inhibiting distinct signaling pathways. We expect that this combination treatment will show low toxicity and high efficacy in patients. Our study supports the use of the combination of low doses of SGI-110 and oxaliplatin in HCC patients.

| S-EPMC5528722 | biostudies-literature

Small RNA sequencing of mouse bone marrow derived extracellular vesicles [EV.sRNA]

Project description:Mouse BM extracellular vesicles were isolated from Ocn-GFP Topaz mice using the Exoeasy and miRneasy (Qiagen). Small RNA libraries were constructed using NEBNext Multiplex Small RNA Library Prep Set for Illumina (New England biolabs). Libraries were sequenced using Hiseq2500 instrument

2021-12-08 | GSE127864 | GEO

Genome-wide gene expression patterns in reprogramming MEF infected by SeVdp vectors carrying KLF4 WT or L507A mutant

Project description:To evaluate global gene expression pattern changes between KLF4 L507A and WT during reprogramming, RNA-Seq was performed on the samples collected from reprogramming MEF infected with SeVdp vectors carrying KLF4 WT or L507A mutant. Original MEF and resulting miPSCs (mouse iPSCs) were also used as samples. RNA-seq library was generated using NEBNext Ultra Directional RNA Library Prep Kit (New England Biolabs) and NEBNext rRNA Delepletion Kit (New England Biolabs) by Lab Droid “Maholo” (Robotic Biology Institute) automatically. Paired-end sequencing of the libraries was performed using Novaseq 6000 SP Sequencing system using SP 100 cycle kit (Illumina). Reads from RNA-seq experiments were mapped to the mouse genome (GRCm38 or mm10) and analyzed for differential gene expression and PCA (principal component analysis) using CLC Genomics Workbench (Qiagen) software.

2021-09-27 | GSE184449 | GEO

Analysis of CAL165 cells transcriptome using RNASeq

Project description:Total RNA extracted from the head and neck cell line CAL165 were purified using miRNeasy minikit (Qiagen). RNA libraries were then generated with the NEB next small library prep set for SOLID (New England Biolabs) and sequenced on the Applied Biosystems SOLiD 5500 wildfire system following the manufacturer's instructions.

2017-06-07 | GSE89510 | GEO

Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma.

Project description:Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

| S-EPMC9162925 | biostudies-literature

The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer.

Project description:PurposeTo investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer.Experimental designSeveral ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR.ResultsWe demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage.ConclusionsThese results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting.

| S-EPMC4268357 | biostudies-literature

Analysis by RNAseq of the transcriptome of different stage of skin carcinogenesis induced by topical application of DMBA/TPA

Project description:Total RNA extracted from biopsies of healthy skin, papilloma, SCC Tumor and of 2 cell lines isolated from these tumors were purified using miRNeasy minikit (Qiagen). RNA libraries were then generated with the NEB next small library prep set for SOLID (New England Biolabs) and sequenced on the Applied Biosystems SOLiD 5500 wildfire system following the manufacturer's instructions.

2017-06-07 | GSE89509 | GEO

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