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Activation of the pyruvate dehydrogenase complex dictates tumour progression in prostate cancer

ABSTRACT: Metabolism in cancer serves to provide energy and key biomolecules that sustain cell growth, a process that is frequently accompanied by decreased mitochondrial use of glucose. Importantly, metabolic intermediates including mitochondrial metabolites are central substrates for post-translational modifications at the core of cellular signalling and epigenetics. However, the molecular means that coordinate the use of mitochondrial metabolites for anabolism and nuclear protein modification are poorly understood. Here, we unexpectedly found that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) that regulates mitochondrial metabolism16 inhibits prostate cancer development in different mouse and human xenograft tumour models. Intriguingly, we found that lipid biosynthesis was strongly affected in prostate tumours upon PDC inactivation. Mechanistically, we found that nuclear PDC controls the expression of Sterol regulatory element-binding transcription factor (SREBF) target genes by mediating histone acetylation whereas mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated effort to sustain anabolism. In line with the oncogenic function of PDC in prostate cancer, we find that PDHA1 and the PDC activator, Pyruvate dehydrogenase phospatase 1 (PDP1), are frequently amplified and overexpressed at both gene and protein level in these tumours. Taken together, our findings demonstrate that both mitochondrial and nuclear PDC sustains prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE74245 | GEO | 2018/02/21

REPOSITORIES: GEO

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Gene expression of HUVECS treated with either siRNA to CTRL or PDHA1 and treated with TNF 16 hours

Project description:The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimulileads to an increase in mitochondrial metabolism, however, the function and regulation of elevated mitochondrial metabolism in EC in response to pro-inflammatory cytokines remains unclear. Using high-resolution metabolomics and13C-glucose labeled flux techniques, we demonstrate thatpyruvate dehydrogenase activity (PDH) and tricarboxylic acid cycle flux is elevated in human umbilical vein ECs (HUVECs) in response to overnight (16 hrs) treatment withTNFα (10 ng/mL).Mechanistic studies indicate thatTNFα mediates these metabolic changes via mitochondrial specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB dependent mechanism. Using RNA sequencing following siRNA mediated knockdown of thecatalytically active subunit of PDH, PDHE1a(PDHA1 gene), we show that PDH fluxcontrols the transcription of approximately one-third of the genes that are upregulated by TNFastimulation. Notably, TNFainduced PDHflux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules.Using metabolomics and ChIP sequencing (H3AcK27), we demonstrate that TNFα induced PDH flux promotes histone acetylation of specific gene sets via citrate accumulation and ATP-citrate lyase activity.Together, these resultsindicate that targeting endothelial glucose oxidation and/or acetyl CoA generation may offer a novel therapeutic strategy in the treatment of vascular inflammation.

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