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
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.
Project description:Genome wide methylation microarray was performed on two RD and Rh30 rhabdomyosarcoma cell lines treated with 0.5µM of the dna methyltrasferase inhibitor SGI-110 for 5 days or DMSO control.
Project description:Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular Inhibitor of Apoptosis Protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS and BAX. Individual knockdown of the death receptors TNFR1, DR5 and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for TRAIL or FASLG failed to provide protection. Also, TNF-blocking antibody Enbrel had little protective effect on SGI110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660 triggered loss of mitochondrial membrane potential (MMP) and BAX activation, which contributes to cell death as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in activation of caspases-3/-7, nuclear fragmentation and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.
Project description:Renal cell carcinoma (RCC) is one of the most common malignant tumors of urinary system. The Food and Drug Administration (FDA) has approved everolimus for the treatment of advanced RCC, but r everolimus resistance limits its application in clinic. We here reported the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 as an inducer of methuosis, a type of cell death form independent of apoptosis. Additionally, SGI-1027 and everolimus worked in concert to suppress the proliferation, migration, and invasion of renal cancer cells while also inducing apoptosis and GSDME-dependent pyroptosis. In vitro transplanted tumor mice models, everolimus combined with SGI-1027 played a significant inhibitory effect on the growth of renal cancer tumors with good tolerance. The objective of this study is to explore the mechanism of the synergistic effect of everolimus and SGI-1027. We demonstrated through analysis of transcriptome high-throughput sequencing data that lysosomes were strongly linked with the synergistic effect of everolimus and SGI-1027 at the transcriptional level, which provides a new strategy for everolimus resistance and the treatment of advanced RCC.
Project description:The majority of bacterial genomes have high coding efficiencies, but there are an few genomes of the intracellular bacteria that have low gene density. The genome of the endosymbiont Sodalis glossinidius contains almost 50% pseudogenes containing mutations that putatively silence them at the genomic level. We have applied multiple omic strategies: combining single molecule DNA-sequencing and annotation; stranded RNA-sequencing and proteome analysis to better understand the transcriptional and translational landscape of Sodalis pseudogenes, and potential mechanisms for their control. Between 53% and 74% of the Sodalis transcriptome remains active in cell-free culture. Mean sense transcription from Coding Domain Sequences (CDS) is four-times greater than that from pseudogenes. Core-genome analysis of six Illumina sequenced Sodalis isolates from different host Glossina species shows pseudogenes make up ~40% of the 2,729 genes in the core genome, suggesting are stable and/or Sodalis is a recent introduction across the Glossina genus as a facultative symbiont. These data further shed light on the importance of transcriptional and translational control in deciphering host-microbe interactions, and demonstrate that pseudogenes are more complex than a simple degrading DNA sequence. For this reason, we show that combining genomics, transcriptomics and proteomics represents an important resource for studying prokaryotic genomes with a view to elucidating evolutionary adaptation to novel environmental niches.
Project description:There is an urgent need for developing more effective therapies for aggressive hepatocellular carcinoma (HCC). Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTis. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials.
