He is an internationally recognized leader in the cancer metabolism filed. His research findings have great potential for improving cancer diagnosis and treatment. He has made the following milestone discoveries: (1) Discoveries of the protein kinase activity of metabolic enzymes, (2) Discoveries of the protein phosphatase activity of metabolic enzymes, (3) elucidation of mechanisms underlying the regulation of the Warburg effect, and (4) revelation of the non-metabolic functions of metabolic enzymes in tumorigenesis.
Discoveries of the protein kinase activity of metabolic enzymes
Lu demonstrated that glycolytic enzyme pyruvate kinase M2 (PKM2) acts as a protein kinase and phosphorylates histone H3 to epigenetically regulate gene expression (Cell, 2012; listed in the 2012 Signaling Breakthroughs of the Year by Science Signaling), the spindle assembly protein Bub3 to regulate chromosome segregation and mitotic checkpoint in metaphase, and myosin light chain (MLC) 2 to promote cytokinesis of cancer cells (Molecular Cell, 2014; Nature Communications, 2014). He also showed that the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) phosphorylates and activates pyruvate dehydrogenase kinase 1 (PDHK1) to repress pyruvate metabolism in mitochondria (Molecular Cell, 2016). Under energy stress conditions, PGK1 phosphorylates Beclin1 to regulate autophagy of cancer cells (Molecular Cell, 2017). In addition, he demonstrated that fructose kinase KHK-A is highly expressed in hepatocellular carcinoma cells by alternate splicing and acts as a protein kinase, phosphorylating and activating phosphoribosyl pyrophosphate synthetase 1 (PRPS1) to promote the de novo nucleic acid synthesis and liver tumor formation (Nature Cell Biology, 2016) and phosphorylating p62 to activate Nrf2-depdenent antioxidant responses (Science Advances, 2019). Furthermore, he discovered that gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) phosphorylates INSIG to activate SREBP and lipogenesis in cancer cells (Nature, 2020). His recent work revealed that choline kinase alpha 2 (CHKα2) phosphorylates PLIN2/3 to promote lipolysis of lipid droplets (Molecular Cell, 2021) and that hexokinase (HK) 2 phosphorylates IκBα to enhance PD-L1 expression and tumor immune evasion (Cell Metabolism, 2022).
Discoveries of the protein phosphatase activity of metabolic enzymes
Lu discovered for the first time that metabolic enzymes can function as protein phosphatase. Fructose-1,6-bisphosphatase 1 (FBP1) dephosphorylates histone H3 at T11 and suppresses gene transcription (Nature Cell Biology, 2022).In addition, FBP1 interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at S227. This dephosphorylation blocks TERT translocation into the nucleus, leading to inhibited telomerase activity, reduced telomere lengths, enhanced senescence, and suppressed tumor growth in mice (Nature Chemical Biology, 2024).
Elucidation of mechanisms of underlying the regulation of the Warburg effect
Lu demonstrated that growth factor receptor activation induces translocation of PKM2 into the nucleus, where it binds to and activates tyrosine-phosphorylated β-catenin and c-Myc, resulting in expression of glycolytic genes and enhanced glucose uptake and lactate production (Nature Cell Biology, 2012; Molecular Cell, 2012). In addition, he showed that activation of growth factor receptors, expression of K-Ras G12V and B-Raf V600E, and hypoxia induce the mitochondrial translocation of PGK1, which phosphorylates and activates PDHK1 to inhibit mitochondrial pyruvate metabolism, thereby promoting the Warburg effect (Molecular Cell, 2016). Furthermore, he discovered that PTEN suppresses aerobic glycolysis by dephosphorylating and Inhibiting autophosphorylated PGK1, and deficiency of PTEN in cancer cells elicits the Warburg effect (Molecular Cell, 2019). Thus, the Warburg effect is regulated by nuclear PKM2, mitochondrial PGK1, and PTEN deficiency-activated cytosolic PGK1 in cancer cells.
Revelation of the non-metabolic functions of metabolic enzymes and metabolites in tumorigenesis
In addition to the findings that metabolic enzymes of PKM2, PGK1, KHK-A, PCK1, and CHKα2 can function as protein kinases, he 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), (c) β-KGDH-associated KAT2A acts as a histone H3 succinyltransferase to regulate gene expression (Nature, 2017), (d) nuclear PGK1 alleviates ADP-dependent inhibition of CDC7 to promote DNA replication (Molecular Cell, 2018), (e) EGFR-phosphorylated platelet isoform of phosphofructokinase 1 (PFPK) activates PI3K in cancer cells (Molecular Cell, 2018), and (f) programmable base editing of mutated TERT promoter inhibits tumor growth (Nature Cell Biology, 2020), and (g) the succinyl-coenzyme A (CoA) synthetase ADP-forming subunit β (SUCLA2) regulates glutaminase succinylation and activity counteracts oxidative stress of tumor cells (Molecular Cell, 2021).
