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SRT1720 Inhibits the Growth of Bladder Cancer in Organoids and Murine Models through the SIRT1-HIF axis

ABSTRACT: SRT1720 Inhibits the Growth of Bladder Cancer in Organoids and Murine Models through the SIRT1-HIF axis

PROVIDER: PRJNA650118 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12363964_1.fastq.gz	Fastqsanger.gz
	SRR12363964_2.fastq.gz	Fastqsanger.gz
	SRR12363965_1.fastq.gz	Fastqsanger.gz
	SRR12363965_2.fastq.gz	Fastqsanger.gz
	SRR12363966_1.fastq.gz	Fastqsanger.gz

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SRT1720 Inhibits the Growth of Bladder Cancer in Organoids and Murine Models through the SIRT1-HIF axis

Project description:Methods: Mouse bladder tumor organoids with Trp53, Pten, Rb1 mutation and Myc, KrasG12D amplification were treated with 10μM SRT1720 and Vehicle for 12 hours respectively. RNA libraries of SRT1720 and vehicle treated mouse bladder organoids were constructed according to standard Illumina protocols, and bulk RNA-seq were performed using Illumina NovaSeq 6000 sequencing platform.

2021-09-01 | GSE155525 | GEO

Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1–HIF-2α axis

Project description:Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1–HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.

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Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1–HIF-2α axis

Project description:Decoupling NAD+ metabolic dependency in chondrosarcoma by targeting the SIRT1–HIF-2α axis

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GETomics based bulk-RNA sequencing revealed HIF-3α prevents COPD by inhibiting alveolar epithelial cell ferroptosis via the HIF-3α-GPx4 axis.

Project description:COPD patients are largely asymptomatic until later stages when prognosis is generally poor. Here, by shifting the focus forward to pre-COPD and smoking stages, we found the peak of reactive oxygen species (ROS) level and hypoxia character are enriched in pre-COPD samples, and hypoxia inducible factor (HIF)-3α is the key factor. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. In this study, by leveraging scRNA-seq and EpCAM co-localization analysis we identified HIF-3α is downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq and RSL3 we found the activation of HIF-3α-GPx4 axis inhibits alveolar epithelial cell ferroptosis under the treatment of cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibits alveolar epithelial cells ferroptosis and prevents the declining of lung function. Our data suggest the activation of HIF-3α-GPx4 axis prevents COPD by inhibiting alveolar epithelial cells ferroptosis. By leveraging this comprehensive analysis method, more promising treatment targets will be found and enhance our understanding to the pathogenesis.

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NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling

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