The Huang Lab
Our research efforts are directed towards understanding the mechanisms by which tumor cells become more and more malignant as they advance, a seemingly inevitable process that underlies therapeutic failure. Malignant progression involves genetic and epigenetic alterations that enable tumor cells to evolve and acquire aggressive malignant properties. Although numerous studies investigate the resultant signaling pathways leading to malignant progression, the mechanisms by which cancer cells acquire genetic and epigenetic changes remain obscure.
Our research focuses on the role of hypoxia (low oxygen tension) in malignant progression. Previous studies from our laboratory first demonstrated that the hypoxia-inducible factor 1α (HIF-1α)1, a master regulator of oxygen homeostasis, induces genetic alterations by inhibiting DNA repair gene expression.2, 3 At the molecular level, we identified a novel HIF-1α–c-Myc pathway4, 5 that accounts for the hypoxic suppression of DNA repair. To test our hypothesis that HIF-1α over-expression drives malignant progression via the induction of genetic instability6, we have been using cell culture and mouse models to ascertain whether activation of the HIF-1α–c-Myc pathway is sufficient to accelerate tumor progression and metastasis.7 Among various types of solid tumors including osteosarcomas and breast cancers, glioblastoma—the most frequently occurring and mostly deadly human intracranial tumor—is of our particular interest because of the presence of extreme hypoxia within the tumor and its salient feature of local infiltration. Immunohistochemical staining of human glioblastomas has revealed that HIF-1α is especially over-expressed in areas surrounding necrosis and at the peripheral where local invasion takes place. The objectives of our research are to demonstrate a HIF-1α mediated mechanism of genetic and epigenetic alteration as the underlying cause of malignant progression; to characterize the responsible molecular pathways; and to develop a novel approach to cancer treatment by targeting mechanisms of genetic and epigenetic alteration.
References
- 1. Huang LE, Bunn HF. Hypoxia-inducible factor and its biomedical relevance. J Biol Chem 2003; 278(22): 19575-19578.
- 2. Koshiji M, To KK, Hammer S, et al. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol Cell 2005; 17(6): 793-803.
- 3. 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; 25(20): 4784-4794.
- 4. Koshiji M, Kageyama Y, Pete EA, et al. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. Embo J 2004; 23(9): 1949-1956.
- 5. Huang LE. Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation. Cell Death Differ 2008; 15(4): 672-677.
- 6. Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability-a calculated mechanism underlying tumor progression. J Mol Med 2007; 85(2): 139-148.
- 7. Yoo YG, Christensen J, Huang LE. HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.Cancer Res 2011; 71(4): 1244-1252.