In the News
Study provides better understanding of how brain tumors ‘feed’
Study reveals PGK1 enzyme as therapeutic target for deadliest brain cancer
Monitoring sugar metabolism in liver may be a key to cancer diagnosis
PGK1 protein promotes brain tumor formation and cancer metabolism
Divide and conquer
MD Anderson study reveals new insight into tumor progression
MD Anderson study reveals new insight into DNA Repair
Professor, Department of Neuro-Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Professor, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
· Cancer metabolism
· Tumorigenesis and tumor progression
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 PKM2, PGK1, and KHK-A and metabolites regulate gene expression, mitosis, cytokinesis, de novo nucleic acid synthesis, and autophagy ( Nature Reviews Molecular Cell Biology, 2018). 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 Gcn5 acts as a histone H3 succinyltransferase to regulate gene expression ( Nature, 2017), and (D) the platelet isoform of phosphofructokinase 1 (PFKP) promotes PI3K activation upon EGFR activation ( Molecular Cell, 2018).
|1998||The Graduate School and University Center, City University of New York, New York, NY, USA, PHD, Molecular, Cellular and Developmental Biology|
|1986||Taishan Medical College, Shandong, CHN, MD, Medicine|
|1999-2003||Research Fellowship, Department of Molecular and Cell Biology, Cancer Center Designated by the National Cancer Institute, The Salk Institute for Biological Studies, La Jolla, CA|
|1986-1992||Physician/Oncologist, Qingdao Hospital, Qingdao|
Research Associate/Postdoctoral Fellow, The Salk Institute for Biological Studies, La Jolla, CA, 1999 - 2003
Physician and Oncologist, Qingdao Hospital, Qingdao, NY, 1986 - 1992
Institutional Committee Activities
Member, The Multidisciplinary Research Advisory Committee (MRAC), 2012 - Present
Chair, The Odyssey Program Advisory Committee, 2011 - Present
Member, Brain Tumor Center (BTC) Research Seminar Series Committee, 2010 - Present
Member, The Cancer Biology Program International Student Admission Committee of Graduate School of Biomedical Sciences (GSBS), 2009 - Present
Member, Brain Tumor Center (BTC) Laboratory Sciences Committee, 2006 - Present
|2017||American Association for the Advancement of Science, Fellow|
|2016||The Dallas/Fort Worth Living Legend Faculty Achievement Award in Basic Research, The University of Texas MD Anderson Cancer Center|
|2015||The Ruby E. Rutherford Distinguished Professorship, The University of Texas MD Anderson Cancer Center|
|2013||The Potu N. Rao Award for Excellence in Basic Science, The University of Texas MD Anderson Cancer Center|
|2012||The James S. McDonnell Foundation Scholar Award, The James S. McDonnell Foundation|
|2011||The Faculty Scholar Award, The University of Texas MD Anderson Cancer Center|
|2009||American Cancer Society Research Scholar, American Cancer Society|
|2008||Peter Steck Memorial Young Investigator Award, Pediatric Brain Tumor Foundation|
|2007||Brain Tumor Society Program Award, Brain Tumor Society|
|2000||California Breast Cancer Research Program Postdoctoral Fellowship, California Breast Cancer Research Program|
|1999||The Pioneer Fund Fellowship, The Salk Institute|
|1997||The Beatrice Goldstein Konheim Graduate Scholarship in the Life Sciences, City University of New York|
- Qian X, Li X, Tan L, Lee JH, Xia Y, Cai Q, Zheng Y, Wang H, Lorenzi PL, Lu Z. Conversion of PRPS Hexamer to Monomer by AMPK-Mediated Phosphorylation Inhibits Nucleotide Synthesis in Response to Energy Stress. Cancer Discov 8(1):94-107, 2018. e-Pub 2017. PMID: 29074724.
- Wang Y, Guo YR, Liu K, Yin Z, Liu R, Xia Y, Tan L, Yang P, Lee JH, Li XJ, Hawke D, Zheng Y, Qian X, Lyu J, He J, Xing D, Tao YJ, Lu Z. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552(7684):273-277, 2017. e-Pub 2017. PMID: 29211711.
- Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, Qian X, Xia Y, Zheng Y, Piao Y, Chen Q, de Groot JF, Jiang T, Lu Z. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun 8(1):949, 2017. e-Pub 2017. PMID: 29038421.
- Li X, Yu W, Qian X, Xia Y, Zheng Y, Lee JH, Li W, Lyu J, Rao G, Zhang X, Qian CN, Rozen SG, Jiang T, Lu Z. Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. Mol Cell 66(5):684-697.e9, 2017. e-Pub 2017. PMID: 28552616.
- Xia Y, Yang W, Fa M, Li X, Wang Y, Jiang Y, Zheng Y, Ji H, Li J, and Lu Z. EGF-induced histone H3 polyubiquitylation and nucleosome disassembly promote gene expression and tumorigenesis. The J of Experimental Medicine 214(6):1843-1855, 2017. e-Pub 2017. PMID: 28507061.
- Li X, Qian X, Peng LX, Jiang Y, Hawke DH, Zheng Y, Xia Y, Lee JH, Cote G, Wang H, Wang L, Qian CN, Lu Z. A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol 18(5):561-71, 2016. e-Pub 2016. PMID: 27088854.
- Li X, Jiang Y, Meisenhelder J, Yang W, Hawke DH, Zheng Y, Xia Y, Aldape K, He J, Hunter T, Wang L, Lu Z. Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis. Mol Cell 61(5):705-19, 2016. PMID: 26942675.
- Ji H, Lee JH, Wang Y, Pang Y, Zhang T, Xia Y, Zhong L, Lyu J, Lu Z. EGFR Phosphorylates FAM129B to promote Ras activation. Proc Natl Acad Sci U S A 113(3):644-649, 2016. e-Pub 2015. PMID: 26721396.
- Liang J, Cao R, Zhang Y, Xia Y, Zheng Y, Li X, Wang L, Yang W, Lu Z. PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nat Commun 7:12431, 2016. e-Pub 2016. PMID: 27485204.
- Zheng Y, Li X, Qian X, Wang Y, Lee JH, Xia Y, Hawke DH, Zhang G, Lyu J, Lu Z. Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation. Nat Cell Biol 17(10):1348-55, 2015. e-Pub 2015. PMID: 26280537.
- Madarampalli B, Yuan Y, Liu D, Lengel K, Xu Y, Li G, Yang J, Liu X, Lu Z, Liu DX. ATF5 Connects the Pericentriolar Materials to the Proximal End of the Mother Centriole. Cell 162(3):580-92, 2015. e-Pub 2015. PMID: 26213385.
- Jiang Y, Wang Y, Wang T, Hawke DH, Zheng Y, Li X, Zhou Q, Majumder S, Bi E, Liu DX, Huang S, Lu Z. PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells. Nat Commun 5:5566, 2014. e-Pub 2014. PMID: 25412762.
- Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You MJ, Koh MY, Cote G, Aldape K, Li Y, Verma IM, Chiao PJ, Lu Z. EGFR-induced and PKC monoubiquitylation-dependent NF-kB activation upregulates PKM2 expression and promotes tumorigenesis. Molecular Cell 48(5):771-84, 2012. e-Pub 2012. PMID: 23123196.
- Yang W, Zheng Y, Xia Y, Ji H, Chen X, Guo F, Lyssiotis CA, Aldape K, Cantley LC, Lu Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nat Cell Biol 14(12):1295-304, 2012. e-Pub 2012. PMID: 23178880.
- Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Alfred Yung WK, Lu Z. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell 150(4):685-696, 2012. PMID: 22901803.
- Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 480(7375):118-22, (2011 Outstanding Research Publication Award at MDACC; Highlighted Cell Leading Edge, Nature SciBX, Science Signaling, Cancer Research, Cell Research, Chinese journal of Cancer, Future Oncology, & Faculty of 1000 Biology.), 2011. PMID: 22056988.
- Ji H, Wang J, Nika H, Hawke D, Keezer S, Ge Q, Fang B, Fang X, Fang D, Litchfield DW, Aldape K, Lu Z. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin. Molecular Cell 36(4):547-59 (Selected as the feature article by Mol Cell and highlighted in Cell and M.D. Anderson News Release), 2009. PMID: 19941816.
- Lu Z, Hunter T. Degradation of activated protein kinases by ubiquitination. Ann Rev Biochem 78:435-75, 2009. PMID: 19489726.
- Zheng Y, Xia Y, Hawke D, Halle M, Tremblay M, Gao X, Zhou X, Aldape K, Cobb M, Xie K, He J, and Lu Z. FAK phosphorylation by ERK primes Ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Molecular Cell 35(1):11-25 (Highlighted in Mol Cell and Faculty of 1000 Biology), 2009. PMID: 19595712.
- Xia Y, Wang J, Liu TJ, Yung WK, Hunter T, Lu Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. (Selected as the feature article by Mol Cell and received MDACC Nycomed GmbH Outstanding Research Publication Award in 2007). Molecular Cell 25(2):219-32, 2007. PMID: 17244530.
- Lu Z, Ghosh S, Wang Z, Hunter T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4(6):499-515 (Highlighted in: Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/The signaling gateway 2004, and Faculty of 1000 Biology), 2003. PMID: 14706341 (Highlighted in: Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/The signaling gateway 2004, and Faculty of 1000 Biology).
- Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Molecular Cell 9(5):945-56, (Highlighted in: Nat Rev Mol Cell Biol 2002;3:473; Nature-Signaling Update/the signaling gateway, 2002; and Faculty of 1000 Biology), 2002. PMID: 12049732.
- Qian X, Li X, Cai Q, Zhang C, Yu Q, Jiang Y, Lee JH, Hawke D, Wang Y, Xia Y, Zheng Y, Jiang BH, Liu DX, Jiang T, Lu Z. Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy. Mol Cell 65(5):917-931. e-Pub 2017. PMID: 28238651.
- Jiang Y, Shen J, Wang Y, Li X, Liu R, Xia Y, Chen Q, Peng G, Lin SY, Lu Z. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol 7(9):1158-68. e-Pub 2015. PMID: 26237645.