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.
We constructed prostate specific Pten; Pdha1 double knockout mice by crossing transgenic mice with flox elements flanking exon 8 of Pten gene and exon 4 and exon 5 of Pdha1 gene. Gene expression profiling analysis and metabolic analysis between Pten; Pdha1 double knockout and Pten knockout tumours were performed to investigate the metabolic pathways altered upon Pdha1 inactivation. Lipidomics analysis between these two genotypes of tumours were performed to reveal the difference on the lipid and cholesterol ester species in response to Pdha1 inactivation.
We found that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) that regulates mitochondrial metabolism 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 gene and protein level in these tumours.
Taken together, our findings demonstrate that mitochondrial and nuclear PDC sustains prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.
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Legal entity responsible for the study
Molecular Oncology, Institute of Oncology Research
All authors have declared no conflicts of interest.