Our research focuses on cancer signaling and metabolism and has made contributions to the cancer metabolism field through the:
- Elucidation of instrumental mechanisms of the Warburg effect
- Discovery of the protein kinase activity of metabolic enzymes
- Revelation of the non-metabolic functions of metabolic enzymes in tumorigenesis
(1) Our work elucidated instrumental mechanisms underlying the growth factor receptor-promoted Warburg effect. We reported that growth factor receptor activation induces translocation of the glycolytic enzyme pyruvate kinase M2 (PKM2) into the nucleus, where it binds to and activates tyrosine-phosphorylated b-catenin (Nature, 2011), phosphorylates histone H3 (Cell, 2012; listed in the 2012 Signaling Breakthroughs of the Year by Science Signaling), upregulating expression of glycolytic genes and enhancing the glucose uptake and lactate production (Nature Cell Biology, 2012; Molecular Cell, 2012). In addition, we revealed that activation of growth factor receptors, expression of K-Ras G12V and B-Raf V600E, and hypoxia induce the mitochondrial translocation of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), which phosphorylates and activates pyruvate dehydrogenase kinase 1 (PDHK1) to inhibit mitochondrial pyruvate metabolism, thereby promoting the Warburg effect (Molecular Cell, 2016). Thus, growth factor receptor activation-promoted Warburg effect is regulated by nuclear PKM2 and mitochondrial PGK1.
(2) Our work discovered that metabolic enzymes (PKM2, PGK1, and fructokinase (KHK)-A) can function as protein kinases. In addition to the discovery of PKM2 acting as a protein kinase to phosphorylate histone, we demonstrated that PKM2 phosphorylates the spindle assembly protein Bub3 to regulate chromosome segregation and mitotic checkpoint in metaphase and phosphorylates myosin light chain 2 to promote cytokinesis (Molecular Cell, 2014; Nature Communications, 2014). We for the first time reported that hepatocellular carcinoma (HCC) cells alternately splices KHK gene and switch KHK expression from high-activity KHK-C to low-activity KHK-A isoform, which acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote the de novo nucleic acid synthesis and HCC formation (Nature Cell Biology, 2016). Besides our first time report that mitochondrial PGK1 phosphorylates and activates PDHK1 to regulate mitochondrial function, we demonstrated that PGK1 under energy stress conditions phosphorylates Beclin1 to regulate autophagy (Molecular Cell, 2017).
(3) Our work revealed that metabolic enzymes can possess nonmetabolic functions in regulation of instrumental cellular activities. We demonstrated that metabolic enzymes of PKM2, PGK1, and KHK-A regulate gene expression, mitosis, cytokinesis, de novo nucleic acid synthesis, and autophagy. In addition, we demonstrated that (a) the metabolic enzyme fumarase regulates DNA repair (Nature Cell Biology, 2015), (b) generation of acetyl-CoA at the promoter regions by nuclear acetyl-CoA synthetase 2 (ACSS2) induces gene expression for lysosomal biogenesis and autophagy (Molecular Cell, 2017), and (c) a-KGDH-associated KAT2A acts as a histone H3 succinyltransferase to regulate gene expression (Nature, 2017).