Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, Hants, UK.
Institute for Life Sciences, University of Southampton, Southampton, Hants, UK.
FEBS Lett. 2020 Sep;594(18):2988-3001. doi: 10.1002/1873-3468.13874. Epub 2020 Jul 15.
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 coregulators 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.
缺氧适应反应是由缺氧诱导因子（HIF）家族转录因子介导的。这些反应包括上调糖酵解以维持 ATP 生成。这也会产生酸性代谢物，需要 HIF 诱导的碳酸酐酶 IX（CAIX）来中和。C 端结合蛋白（CtBPs）是基因转录的核心调节剂，由于它们受糖酵解辅酶 NADH 的调节，因此将糖酵解与基因转录偶联。在这里，我们通过多种互补方法发现，在乳腺癌细胞中对糖酵解和 CtBP 功能的实验操作支持了一种假说，即通过涉及 CtBPs 的机制，已知的 HIF 诱导基因的表达，特别是 CAIX，会适应微环境中的可用葡萄糖。这条新途径促进了缺氧条件下干细胞样癌细胞（SCLC）的存活。
