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L. Eric Huang

Associate Professor of Neurosurgery and
Adjunct Associate Professor of Oncological Sciences

Eric Huang

M.D. Shanghai Medical University, China

Ph.D. Rutgers University

Research

References

eric.huang@hsc.utah.edu

Eric Huang's Lab Page

Eric Huang's PubMed Literature Search

Molecular Biology Program

Brain tumor; cancer metabolism; epigenetic and genetic alterations; hypoxia; tumor progression

Research

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:

Tumor Hypoxia
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.

Glioma Metabolism
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.

IDH-mutant Glioma
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.

References

  1. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem. 2003 May 30;278(22):19575-8. Epub 2003 Mar 14. Review. PubMed PMID: 12639949.
  2. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004 May 5;23(9):1949-56. Epub 2004 Apr 8. PubMed PMID: 15071503; PubMed Central PMCID: PMC404317.
  3. Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P, Huang LE. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell. 2005 Mar 18;17(6):793-803. PubMed PMID: 15780936.
  4. To KK, Sedelnikova OA, Samons M, Bonner WM, Huang LE. The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression. EMBO J. 2006 Oct 18;25(20):4784-94. Epub 2006 Oct 5. PubMed PMID: 17024177; PubMed Central PMCID: PMC1618093.
  5. Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression. J Mol Med (Berl). 2007 Feb;85(2):139-48. Epub 2006 Dec 20. Review. PubMed PMID: 17180667.
  6. Huang LE. Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ. 2008 Apr;15(4):672-7. doi: 10.1038/sj.cdd.4402302. Epub 2008 Jan 11. Review. PubMed PMID: 18188166.
  7. Yoo YG, Christensen J, Gu J, Huang LE. HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression. Sci Signal. 2011 Jun 21;4(178):pt4. doi: 10.1126/scisignal.2002072. PubMed PMID: 21693763.
  8. Huang LE. Biochemistry. How HIF-1α handles stress. Science. 2013 Mar 15;339(6125):1285-6. doi: 10.1126/science.1236966. PubMed PMID: 23493703.
  9. Tiburcio PD, Choi H, Huang LE. Complex role of HIF in cancer: the known, the unknown, and the unexpected. Hypoxia (Auckl). 2014 Jun 18;2:59-70. eCollection 2014. Review. PubMed PMID: 27774467; PubMed Central PMCID: PMC5045057.
  10. Choi H, Gillespie DL, Berg S, Rice C, Couldwell S, Gu J, Colman H, Jensen RL, Huang LE. Intermittent induction of HIF-1α produces lasting effects on malignant progression independent of its continued expression. PLoS One. 2015 Apr 20;10(4):e0125125. doi: 10.1371/journal.pone.0125125. eCollection 2015. PubMed PMID: 25893706; PubMed Central PMCID: PMC4404255.
  11. Karsy M, Guan J, Jensen R, Huang LE, Colman H. The Impact of Hypoxia and Mesenchymal Transition on Glioblastoma Pathogenesis and Cancer Stem Cells Regulation. World Neurosurg. 2016 Apr;88:222-36. doi: 10.1016/j.wneu.2015.12.032. Epub 2015 Dec 25. Review. PubMed PMID: 26724617.
  12. Huang LE, Cohen AL, Colman H, Jensen RL, Fults DW, Couldwell WT. IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget. 2017 Jan 3;8(1):191-202. doi: 10.18632/oncotarget.13329. PubMed PMID: 27852048; PubMed Central PMCID: PMC5352106.

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Last Updated: 8/21/17