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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

ABSTRACT: Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

PROVIDER: PRJNA678735 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13068246_1.fastq.gz	Fastqsanger.gz
	SRR13068246_2.fastq.gz	Fastqsanger.gz
	SRR13068247_1.fastq.gz	Fastqsanger.gz
	SRR13068247_2.fastq.gz	Fastqsanger.gz
	SRR13068248_1.fastq.gz	Fastqsanger.gz

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

Project description:By integration of transcriptome, CHIP-seq, ATAC-seq, proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1α, a master regulator of oxidative metabolism, upon AURKA inhibition. Chromatin immunoprecipitation experiments confirmed binding of c-Myc to the promoter region of PGC1α, which is abrogated by AURKA inhibition and in turn unleashed PGC1α expression. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with inhibitors of FAO (etomoxir) and electron transport chain (gamitrinib) and found substantial synergistic growth inhibition in patient derived xenograft in vitro and extension of overall survival without induction of toxicity in normal tissue.

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

| PRJNA678729 | ENA

Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

Project description:Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

| PRJNA678736 | ENA

AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

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AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:We described the metabolic alterations in glioblastoma model systems elicited by AURKA inhibition. By utilizing proteomic and transcriptomic analyses coupled with untargeted polar and nonpolar metabolite analysis by LC/MC, we found that AURKA inhibition leads to a profound reprogramming of tumor metabolism, which suppresses c-Myc protein levels and increases pro-survival PGC1α which in concert mediate a suppression of glycolysis and a concomitant activation of oxidative phosphorylation (OXPHOS) that is fueled by enhanced fatty acid oxidation (FAO). We targeted these metabolic aberrations with novel combination therapies involving clinical approved drugs in glioblastoma system both in vitro and in vivo. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated and down-regulated genes in Alisertib resistant cells.

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-01 | GSE161574 | GEO

Microarray analysis of skeletal muscle in PGC1α transgenic mice

Project description:Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC1α) is a coactivator of various nuclear receptors and other transcription factors that shows increased expression in skeletal muscle during exercise. In skeletal muscle, PGC1α is considered to be involved in contractile protein function, mitochondrial function, metabolic regulation, intracellular signaling, and transcriptional responses. Several isoforms of PGC1α mRNA have recently been identified. PGC1α-a is a full-length isoform of PGC1α that was the first to be isolated. PGC1α-b is another isoform of PGC1α, which is considered to be similar in function to PGC1α-a, differing by only 16 amino acids at the amino terminus. We have previously generated independent lines of transgenic mice that overexpress PGC1α-a or PGC1α-b in skeletal muscle. The microarray data shows that energy metabolism-related pathways such as the TCA cycle, branched-chain amino acid metabolism, purine nucleotide pathway, and malate–aspartate shuttle are activated in PGC1α transgenic mice compared with wild-type mice. For microarray analysis, RNA was isolated from the gastrocnemius skeletal muscle of wild-type control mice (12 weeks of age) as well as transgenic mice [PGC1α-a (E) (Miura et al., J. Biol. Chem. 278:31385-90, 2003), 12 weeks of age; PGC1α-b (02-1) (Miura et al., Endocrinology 149:4527-33, 2008), 14 weeks of age; and PGC1α-b (03-2) (Miura et al., Endocrinology 2008), 14 weeks of age]. Samples from wild-type and transgenic mice (N = 5 for each group) were pooled before use.

2015-09-18 | E-GEOD-67049 | biostudies-arrayexpress

Synthetic lethality by TET-dioxygenase inhibition

Project description:Synthetic lethality by TET-dioxygenase inhibition

| PRJNA682029 | ENA

MET Inhibition Elicits PGC1α Dependent Metabolic Reprogramming in Glioblastoma

Project description:MET Inhibition Elicits PGC1α Dependent Metabolic Reprogramming in Glioblastoma

| PRJNA556029 | ENA