<p>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:</p>
<p> 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 <em>in vivo</em> 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.</p>
<p> 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, <em>MPC1</em> 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. </p>
<p> The cytosolic isocitrate dehydrogenase 1 gene (<em>IDH1</em>) catalyzes the conversion of isocitrate to 2-oxoglutarate concomitant with the production of NADPH. <em>IDH1 </em>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 <em>IDH1 </em>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.</p>
Harvard Medical School, Brigham & Women's Hospital
Fudan University Shanghai Cancer Center (formerly Shanghai Medical University Cancer Hospital)
Shanghai Medical College of Fudan University (formerly Shanghai Medical University)
- Huang LE (2022). Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma. Biomedicines, 10(2).
- Murnyak B, Huang LE (2021). Association of TP53 Alteration with Tissue Specificity and Patient Outcome of IDH1-Mutant Glioma. Cells, 10(8).
- Tiburcio PDB, Locke MC, Bhaskara S, Chandrasekharan MB, Huang LE (2020). The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma. Transl Oncol, 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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, 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.
- Huang LE (2013). Biochemistry. How HIF-1α handles stress. Science, 339(6125), 1285-6.
- Johnson RS, Huang LE (2007). Can irradiated tumors take NO for an answer? Mol Cell, 26(2), 157-8.
- 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.