Pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis, is instrumental in tumorigenesis. In additionto its well-studied role in cell metabolism, PKM2 promotes cell proliferation though an unknown mechanism. Our recent published and preliminary data show that activation of EGFR results in PKM2 translocation into the nucleus, where PKM2 interacts with ?-catenin and mediates ?-catenin-transactivation. In addition, PKM2 phosphorylates histone H3 and Bub3, subsequently regulating gene transcription and cell mitosis, respectively. We hypothesize that PKM2 has an essential role in controlling gene expression and different phases of cell cycle progression, which is instrumental in EGFR activation-promoted tumor development.
In Specific Aim 1, we will further elucidate the mechanisms underlying PKM2-mediated gene transcription and identify PKM2-regulated expression of genes in cancer cells by genome-wide screening.
In Specific Aim 2, we will elucidate the mechanisms underlying PKM2-regulated chromosome segregation.
In Specific Aim 3, we will determine the role of PKM2- regulated gene transcription and chromosome segregation in EGFR-promoted tumorigenesis. We expect that our proposed research will provide important and previously unrevealed mechanisms of EGFR-promoted tumor development via nonmetabolic functions of PKM2. Building on our findings, therapeutic strategies targeting PKM2-regulated gene expression may be developed to enhance current EGFR-based cancer therapies.
The pyruvate kinase isozyme type M2 (PKM2) isoform, which regulates the rate-limiting final step of glycolysis, promotes cell proliferation through largely unknown mechanisms. The goal of our proposed study is to elucidate the nonmetabolic functions of PKM2 in controlling gene expression. This research is relevant to public health because it may help to identify molecular markers of prognosis and lead to more effective cancer therapies.
|Qian, Xu; Li, Xinjian; Tan, Lin et al. (2018) Conversion of PRPS Hexamer to Monomer by AMPK-Mediated Phosphorylation Inhibits Nucleotide Synthesis in Response to Energy Stress. Cancer Discov 8:94-107|
|Lee, Jong-Ho; Liu, Rui; Li, Jing et al. (2018) EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation. Mol Cell 70:197-210.e7|
|Lu, Zhimin; Hunter, Tony (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci 43:301-310|
|Li, Xinjian; Qian, Xu; Lu, Zhimin (2017) Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy 13:1790-1791|
|Xia, Yan; Yang, Weiwei; Fa, Ming et al. (2017) RNF8 mediates histone H3 ubiquitylation and promotes glycolysis and tumorigenesis. J Exp Med 214:1843-1855|
|Lee, Jong-Ho; Liu, Rui; Li, Jing et al. (2017) Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun 8:949|
|Qian, Xu; Li, Xinjian; Lu, Zhimin (2017) Protein kinase activity of the glycolytic enzyme PGK1 regulates autophagy to promote tumorigenesis. Autophagy 13:1246-1247|
|Wang, Yugang; Guo, Yusong R; Liu, Ke et al. (2017) KAT2A coupled with the ?-KGDH complex acts as a histone H3 succinyltransferase. Nature 552:273-277|
|Li, Xinjian; Yu, Willie; Qian, Xu et al. (2017) Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Mol Cell 66:684-697.e9|
|Qian, Xu; Li, Xinjian; Cai, Qingsong et al. (2017) Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy. Mol Cell 65:917-931.e6|
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