Glycolysis, via NADH-dependent dimerisation of CtBPs, regulates hypoxia-induced expression of CAIX and stem-like breast cancer cell survival.

Adaptive responses to hypoxia are mediated by the hypoxia-inducible factor (HIF) family of transcription factors. These responses include the upregulation of glycolysis to maintain ATP production. This also generates acidic metabolites, which require HIF-induced carbonic anhydrase IX (CAIX) for their neutralisation. C-terminal binding proteins (CtBPs) are co-regulators of gene transcription and couple glycolysis with gene transcription due to their regulation by the glycolytic coenzyme NADH. Here, we find that experimental manipulation of glycolysis and CtBP function in breast cancer cells through multiple complementary approaches supports a hypothesis whereby the expression of known HIF-inducible genes, and CAIX in particular, adapts to available glucose in the microenvironment through a mechanism involving CtBPs. This novel pathway promotes the survival of stem cell-like cancer (SCLC) cells in hypoxia.