L. Eric Huang, MD, PhD
- Brain Tumors
- Cancer Metabolism
- Disease Progression
- Epigenetics in Cancer
- Genetic Instability
- Isocitrate Dehydrogenase
- Mouse Models of Cancer
- Risk Factors
- Departments: Neurosurgery - Associate Professor, Oncological Sciences - Adjunct Associate Professor
- Divisions: Adult Neurosurgery
- Cancer Center Programs: Nuclear Control of Cell Growth & Differentiation
Academic Office Information
Clinical Neurosciences Center
175 North Medical Drive East, Room: 3335A
Salt Lake City, UT 84132
Dr. Huang received his MD degree from the Shanghai Medical University, Shanghai, China in 1984. Following this he was a resident in Tumor Pathology at the Cancer Hospital-Shanghai Medical University in China between1984-1986. He then went on to complete his Ph.D. in 1994, in the area of cell and developmental biology from Rutgers University. Dr. Huang received postdoctoral training at the Brigham and Women’s Hospital, Harvard Medical School as a Research Fellow between 1994-1997. Following this, for approximately three years, Dr. Huang stayed on as an Instructor in Medicine at Harvard Medical School. In 2000 Dr. Huang became a principal investigator at the National Institute of Health in Bethesda, MD and Head of the Hypoxia and Tumorigenesis Unit, Laboratory of Carcinogenesis, National Cancer Institute, National Institutes of Health.
Our research efforts are directed towards understanding the mechanisms underlying malignant progression, a seemingly inevitable process that results in therapeutic failure and patient death. Malignant progression requires genetic, epigenetic, and metabolic alterations that enable tumor cells to evolve and acquire aggressive malignant properties. My lab focuses on malignant progression of glioma, the most common and deadly form of human brain cancers, by conducting research in the following areas:
Previous studies from my lab and others have indicated a critical role for hypoxia (low oxygen tension) in malignant progression. We first demonstrated in cell culture models that the hypoxia-inducible factor 1α (HIF-1α), a master regulator of oxygen homeostasis, induces genetic alterations by inhibiting DNA repair. At the molecular level, we identified a novel mechanism that accounts for the hypoxic suppression of DNA repair via the Myc pathway. To demonstrate in vivo effects of HIF-1α on genetic alteration, we have adopted the RACS/TVA mouse model to test our hypothesis that HIF-1α overexpression drives glioma progression by inducing genetic alteration.
Metabolic reprogramming is an adaptive response critical for the survival and proliferation of cancer cells through the reduction of glucose oxidation (the Warburg effect) and diversion of glycolytic metabolites for the synthesis of macromolecules. The mitochondrial pyruvate carrier (MPC) protein complex, consisting of MPC1 and MPC2, is essential for pyruvate transport into mitochondria. In most human cancers, MPC1 is frequently deleted or down-regulated and, furthermore, the MPC activity is low, which is consistent with the concept of Warburg effect. The role of MPC in malignant glioma, however, seems more complex, as indicated by our bioinformatics analysis of patient data and experimental data. We hypothesize the cerebral cortex provides a unique microenvironment for tumor cell survival and we are actively testing this hypothesis in order to identify metabolic vulnerabilities of glioma cells that can be used for therapeutic intervention.
The cytosolic isocitrate dehydrogenase 1 gene (IDH1) catalyzes the conversion of isocitrate to 2-oxoglutarate concomitant with the production of NADPH. IDH1 mutations at Arg132 are most common in human glioma, particularly in lower-grade gliomas. Mutant IDH1 converts 2-oxoglutarate to 2-hydroxyglutarate, a potent inhibitor of 2-oxoglutarate-dependent histone demethylases and the TET family of 5-methylcytosine hydroxylases. Consequently, IDH-mutant gliomas exhibit a CpG island methylator phenotype resulting from histone and DNA hypermethylation. The current prevailing hypothesis is that mutant IDH1 acts as an oncogenic driver of glioma genesis, which is difficult to account for much improved overall survival of patients with IDH-mutant glioma than those with IDH-wildtype glioma. Our analysis of patient and experimental data, however, has led to a disparate hypothesis, i.e., the mutation of IDH1 is a protective response from the affected cells to retard oncogenic transformation and progression, yet attenuation of the epigenetic change is likely an escape mechanism that drives eventual progression of glioma. We have devised various approaches to the test of our hypothesis and furthermore have developed an interest in identifying risk factors specific to IDH-mutant patients for early intervention.
|Postdoctoral Fellowship||Harvard Medical School, Brigham & Women's Hospital
|Doctoral Training||Rutgers University
Cell and Developmental Biology
|Graduate Training||Rutgers University
|Residency||Shanghai Medical University Cancer Hospital
|Professional Medical||Shanghai Medical University
|Residency||Shanghai Medical University Cancer Hospital
|Professional Medical||Shanghai Medical University
Selected Provider Publications
Huang LE eds (01/13/2018). Hypoxia - Methods and Protocols. Methods in Molecular Biology. (Vol. 1742). New York: Humana Press.
Global Impact: Global.
Awards & Honors
|Den-Mei Brain Tumor Education Foundation Award, Taipei, Republic of China||Asia|
|Latest Understanding of Malignant Glioma, Nanchang Second Affiliate Hospital, Nanchang University, Nanchang, Jiangxi, China||China|
|Latest Understanding of Malignant Glioma, People's Hospital of Shangrao City, Shangrao, Jiangxi, China||China|
|06/16/2015||Committee Member||Member of the Genomics and Biodiversity Commission for the 38th World Congress of International Union of Physiological Sciences||Global|
|08/28/2010||Committee Member||Member of the Genomics and Biodiversity Commission for the 37th World Congress of International Union of Physiological Sciences||Global|
- Tiburcio PDB, Locke MC, Bhaskara S, Chandrasekharan MB, Huang LE (2020). The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma. Translational Oncology, 13(10), 100819.
- Tiburcio PDB, Gillespie DL, Jensen RL, Huang LE (2020). Extracellular glutamate and IDH1R132H inhibitor promote glioma growth by boosting redox potential. J Neurooncol, 146(3), 427-437.
- Huang LE (2019). Friend or foe-IDH1 mutations in glioma 10 years on. Carcinogenesis, 40(11), 1299-1307.
- Karsy M, Guan J, Huang LE (2018). Prognostic role of mitochondrial pyruvate carrier in isocitrate dehydrogenase-mutant glioma. J Neurosurg, 130(1), 56-66.
- Tiburcio PDB, Xiao B, Berg S, Asper S, Lyne S, Zhang Y, Zhu X, Yan H, Huang LE (2018). Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis. Acta Neuropathol, 135(2), 285-298.
- Tiburcio PD, Lyne SB, Huang LE (2018). In vivo manipulation of HIF-1alpha expression during glioma genesis. Methods Mol Biol, 1742, 227-235.
- Huang LE, Cohen AL, Colman H, Jensen RL, Fults DW, Couldwell WT (2017). IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget, 8(1), 191-202.
- Karsy M, Guan J, Jensen R, Huang LE, Colman H (2016). The Impact of Hypoxia and Mesenchymal Transition on Glioblastoma Pathogenesis and Cancer Stem Cells Regulation. World Neurosurg, 88, 222-236.
- Choi H, Gillespie DL, Berg S, Rice C, Couldwell S, Gu J, Colman H, Jensen RL, Huang LE (2015). Intermittent induction of HIF-1α produces lasting effects on malignant progression independent of its continued expression. PLoS ONE, 10(4), e0125125.
- Tiburcio PD, Choi H, Huang LE (2014). Complex role of HIF in cancer: the known, the unknown, and the unexpected. Hypoxia (Auckl), 2, 59-70.
- Huang LE (2013). Biochemistry. How HIF-1α handles stress. 339(6125), 1285-6.
- Hayashi M, Yoo YY, Christensen J, Huang LE (2011). Requirement of evading apoptosis for HIF-1α-induced malignant progression in mouse cells. Cell Cycle, 10(14), 2364-72.
- Yoo YG, Christensen J, Gu J, Huang LE (2011). HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression. Sci Signal, 4(178), pt4.
- Yoo YG, Christensen J, Huang LE (2011). HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function. Cancer Res, 71(4), 1244-52.
- Rice C, Huang LE (2010). From antiangiogenesis to hypoxia: current research and future directions. Cancer Manag Res, 3, 9-16.
- Yoo YG, Hayashi M, Christensen J, Huang LE (2009). An essential role of the HIF-1alpha-c-Myc axis in malignant progression. Ann N Y Acad Sci, 1177, 198-204.
- Huang LE (2008). Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ, 15(4), 672-7.
- Hammer S, To KK, Yoo YG, Koshiji M, Huang LE (2007). Hypoxic suppression of the cell cycle gene CDC25A in tumor cells. Cell Cycle, 6(15), 1919-26.
- Huang LE, Bindra RS, Glazer PM, Harris AL (2006). Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression. J Mol Med, 85(2), 139-48.
- Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W (2006). Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A, 103(49), 18727-32.
- To KK, Sedelnikova OA, Samons M, Bonner WM, Huang LE (2006). The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression. EMBO J, 25(20), 4784-94.
- To KK, Huang LE (2005). Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. J Biol Chem, 280(45), 38102-7.
- To KK, Koshiji M, Hammer S, Huang LE (2005). Genetic instability: the dark side of the hypoxic response. Cell Cycle, 4(7), 881-2.
- Wang V, Davis DA, Haque M, Huang LE, Yarchoan R (2005). Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res, 65(8), 3299-306.
- Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P, Huang LE (2005). HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell, 17(6), 793-803.
- Koshiji M, Huang LE (2004). Dynamic balancing of the dual nature of HIF-1alpha for cell survival. Cell Cycle, 3(7), 853-4.
- Kageyama Y, Koshiji M, To KK, Tian YM, Ratcliffe PJ, Huang LE (2004). Leu-574 of human HIF-1alpha is a molecular determinant of prolyl hydroxylation. FASEB J, 18(9), 1028-30.
- Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2004). HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J, 23(9), 1949-56.
- Huang LE, Pete EA, Schau M, Milligan J, Gu J (2002). Leu-574 of HIF-1alpha is essential for the von Hippel-Lindau (VHL)-mediated degradation pathway. J Biol Chem, 277(44), 41750-5.
- Elson DA, Thurston G, Huang LE, Ginzinger DG, McDonald DM, Johnson RS, Arbeit JM (2001). Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev, 15(19), 2520-32.
- Gu J, Milligan J, Huang LE (2001). Molecular mechanism of hypoxia-inducible factor 1alpha -p300 interaction. A leucine-rich interface regulated by a single cysteine. J Biol Chem, 276(5), 3550-4.
- Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol, 2(7), 423-7.
- Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF (1999). Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem, 274(13), 9038-44.
- Huang LE, Gu J, Schau M, Bunn HF (1998). Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A, 95(14), 7987-92.
- Huang LE, Arany Z, Livingston DM, Bunn HF (1996). Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem, 271(50), 32253-9.
- Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996). An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci U S A, 93(23), 12969-73.
- Huang LE, Bunn HF (2003). Hypoxia-inducible factor and its biomedical relevance. [Review]. J Biol Chem, 278(22), 19575-8.
- Huang LE eds (01/13/2018). Hypoxia - Methods and Protocols. Methods in Molecular Biology. (Vol. 1742). New York: Humana Press.
- Huang LE, Yoo YG, Koshiji M, To KKW (2011). Hypoxia inhibits DNA repair to promote malignant progression. In S. Vengrova (Ed.), DNA Repair and Human Health (pp. 339-348, Chapter 11). Rieka, Croatia: Intech.
- Huang LE, Bunn HF (1998). Regulation of hypoxia inducible factor 1 activity. In Lopez-Barneo J, Weik EK (Eds.), Oxygen regulation of ion channels and gene expression (pp. 101-112). New York, Futura.
- Kaufman B, Scharf O, Arbeit J, Ashcroft M, Brown JM, Bruick RK, Chapman JD, Evans SM, Giaccia AJ, Huang LE, Johnson R, Kaelin W Jr, Koch CJ, Maxwell P, Mitchell J, Neckers L, Powis G, Rajendran J, Semenza GL, Simon J, Storkebaum E, Welch MJ, Whitelaw M, Melillo G, Ivy SP (2004). Proceedings of the Oxygen Homeostasis/Hypoxia Meeting. Cancer Res, 64, 3350-3356.
- Johnson RS, Huang LE (2007). Can irradiated tumors take NO for an answer? Mol Cell, 26(2), 157-8.
- Huang LE (2004). Targeting HIF-alpha: when a magic arrow hits the bull's eye. Drug Discov Today, 9(20), 869.
- Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2005). A Novel HIF-1alpha-Myc Pathway Regulating Hypoxia-induced Cell-cycle Arrest. Frontiers In Science (May 2005, pp. 11-12). Bethesda: National Cancer Institute's Center for Cancer Research.
- Huang LE (2002). Leu574 of HIF-1alpha as a molecular basis for therapeutic development. Employee Invention Report.
- Huang LE (2002). Hypoxia-Inducible Factor 1alpha Variants and Methods of Use.