| Summary: | <p>While the deregulation of cancer metabolism through oncogenic signalling, and the effect of the latter on proliferation and cell cycle control are widely studied, little is known on how metabolism in cancer cells leads to cell cycle control and progression. This project aimed to identify metabolic genes whose inhibition causes cell cycle arrest, which would allow further study of candidate genes in the context of cancer metabolism and cell proliferation. The screen was conducted with a custom siRNA library targeting metabolic genes commonly amplified in primary tumours, as well as those known to be involved in the key regulatory points of metabolic pathways. </p> <p>Results show that TCA cycle, fatty acid metabolism and nucleotide metabolism are especially important during the transition into S phase, whereas enzymes of electron transport chain, glycolysis and pentose phosphate pathway are significant for the completion of both G1 and G2 phases. Among the genes whose knockdown caused G1, cone phosphodiesterase 6H (PDE6H) of the retina was selected for further study as a novel controller of cancer cell cycle and metabolism, recognised for a role in controlling retinal metabolism.</p> <p>Besides causing G1 cell cycle arrest and disruption of G1/S checkpoint mechanism, PDE6H knockdown induced apoptosis and mitochondrial dysfunction. PDE6H depletion also inhibited cell proliferation and lowered basal levels of cellular metabolism. In xenograft experiments of PDE6H CRISPR/Cas9 knockout HCT116 cells we showed that PDE6H deletion slowed down tumour growth and improved animal survival. PDE6 inhibition via a drug, zaprinast, caused similar increase in tumour hypoxia and necrosis as well as an inhibition of tumour cell proliferation. Our results report PDE6H as a controller of cancer cell metabolism and proliferation, making it a potential target for therapy.</p>
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