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GOT1 primes the cellular response to hypoxia by supporting glycolysis and HIF1α stabilisation

Anastasiou, D.; Grimm, F.; Asuaje, A.; Jain, A.; Silva dos Santos, M.; Kleinjung, J.; Nunes, P. M.; Gehrig, S.; Fets, L.; MacRae, J.

2023-09-07 cancer biology
10.1101/2023.09.06.556522 bioRxiv
Show abstract

Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia inducible factor 1a (HIF1) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, prior to full activation of HIF1, remain poorly understood. Here we show that aspartate transaminase 1 (GOT1), which supports NAD+ production by malate dehydrogenase 1 (MDH1), is required, in addition to reserve lactate dehydrogenase (LDH) capacity, for the HIF1-independent increase in glycolysis we observe early upon exposure of cells to hypoxia. Additionally, GOT1 maintains low -ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1 stabilisation in early hypoxia and robust HIF1 target gene expression in later hypoxia. Our findings reveal that, in normoxia, GOT1 maintains cells in a primed state and ready to support increased glycolysis and HIF1 stabilisation upon oxygen limitation, until other adaptive processes that require more time, are fully established.

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