The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

I kappa B kinase epsilon (IKK epsilon) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NF kappa B and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKK epsilon remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKK epsilon orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKK epsilon upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose-derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKK epsilon-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKK epsilon and PSAT1 are both overexpressed, corroborating the link between IKK epsilon and the SBP in the clinical context.