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
Precise regulation of cellular signaling is important for cell growth and differentiation, cell metabolism, apoptosis, and organ and tissue development; dysregulation of cell signaling can lead to the development of cancer. In my laboratory, we study cancer metabolism, tumorigenesis, and tumor progression, focusing on the following research topics:Understanding how cancer advances by altering cell metabolism. Cancer cells have increased glucose uptake and elevated lactic acid production under aerobic conditions, which is termed the Warburg effect. Our research has revealed that pyruvate kinase M2 (PKM2), a glycolytic enzyme upregulated by NF- k B-dependent transcription ( Molecular Cell, 2012), has an essential nuclear function in directly regulating β-catenin transactivation. These findings demonstrate that nuclear b ‑catenin is transactivated via distinct mechanisms in response to growth factor or Wnt signaling. ( Nature, 2011). In addition, we discovered that PKM2 functioning as a protein kinase phosphorylates histone H3-T11, leading to H3-K9 acetylation, gene transcription, and cell cycle progression ( Cell, 2012; highlighted in Science Signaling as a Signaling Breakthrough of the Year). This discovery demonstrates that a key glycolytic enzyme functions as a histone kinase and epigenetically regulates gene transcription in cancer cells. Furthermore, we have elucidated that nuclear PKM2 promotes the Warburg effect via a positive feedback mechanism by upregulating GLUT1, LDHA, and PKM2 expression ( Nature Cell Biology, 2012). Our recent studies demonstrate that PKM2 regulates chromosome segregation and mitotic progression of tumor cells by phosphorylation of Bub3 ( Molecular Cell, 2014) and cytokinesis by phosphorylation of MLC2 ( Nature Communications, 2014). In addition, the finding that metabolic enzymes process critical non-metabolic functions is also evidenced by irradation-induced translocation of fumarase to the DNA damage regions, where fumarase-generated fumarate inhibits H3K36me2 demethylation and promotes DNA repairs by NHEJ ( Nature Cell Biology, 2015). These studies systematically elucidate the mechanisms underlying a growth factor-promoted Warburg effect and the metabolic and non-metabolic functions of PKM2 and fumarase in tumor development and DNA repair. Understanding how cancer cells advance by altering microenvironment. We have identified macrophage migration inhibitory factor (MIF) as an extracellular antagonist of human EGFR. We found that the naturally secreted and O-GlcNAcylated MIF binds to EGFR, thereby inhibiting the binding of EGF to EGFR and EGF-induced EGFR activation. Activation of EGFR enhances the secretion of the MMP13, which degrades extracellular MIF, and results in abrogation of the negative regulation of MIF on EGFR. The finding that EGFR activation downregulates its antagonist in the tumor microenvironment represents an important feedforward mechanism for human tumor cells to enhance EGFR signaling and promote tumorigenesis (Nature Cell Biology, 2015). In addition, we have found that EGFR activation promotes tumor cell invasion and metastasis by disrupting cell–cell contact, which is mediated by caveolae-dependent endocytosis of E-cadherin, Snail-regulated transcriptional repression of E-cadherin, and activation of signaling molecules in caveolae ( Cancer Cell, 2003). Importantly, EGFR activation initiates intracellular crosstalk between EGFR- and Wnt-induced signaling pathways and promotes b -catenin transactivation by releasing b -catenin from cell adhesion complexes. This regulation is accomplished by the disruption of the E-cadherin– b -catenin interaction mediated by AKT-dependent b -catenin phosphorylation and abrogation of the b -catenin and a -catenin interaction mediated by CK2-dependent a -catenin phosphorylation ( Molecular Cell, 2009). Furthermore, the activation of EGFR or Ras reduces focal adhesion by PTP-PEST-dependent dephosphorylation and inhibition of the focal adhesion kinase (FAK) ( Molecular Cell, 2009). The combination of disrupted cell–cell contact, reduced cell–extracellular matrix (ECM) interaction, and accelerated turnover of focal contacts promotes tumor cell migration, invasion, and metastasis. Understanding how cancer progresses by promoting cell survival. In our research on the regulation of cell survival and apoptosis, we have found that c-Jun, a major transcription factor in the activating protein 1 (AP-1) family, is downregulated in response to stress stimulation and chemotherapeutic drug treatment. The downregulation of c-Jun, which is regulated by MEKK1 (functioning as a MAP kinase kinase kinase and an E3 ligase)-mediated ubiquitination ( Molecular Cell, 2002) and HDAC3-dependent transcriptional repression, promotes cell apoptosis ( Molecular Cell, 2007). Differential regulation of c-Jun protein plays an instrumental role in the chemoresistance of cancer cells.
|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.