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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA169603-02
Application #
8639502
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$322,040
Indirect Cost
$120,765
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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

Showing the most recent 10 out of 26 publications