Chun Zhang Yang, Ph.D.
Our group has been intensively investigating tumor genetics and biochemistry and made significant contributions to the understanding of relevant genes in human disorders. For example, we deeply investigated patients with similar tumor manifestations, intrigued by a potential genetic basis underlying their symptoms. This led to a novel discovery of a cluster of mutations in the gene encoding human hypoxia-inducible factor 2α (HIF-2α). Through proteomic approaches and biochemistry assays, we demonstrated that these mutations were necessary and sufficient to promote tumorigenesis and concurrent polycythemia through the introduction of a pseudo-hypoxic phenotype in the tumor cells. This striking finding was reported in original research articles published in the New England Journal of Medicine, which immediately received widespread attention in the fields of tumor genetics and hematology. Since our initial findings, we have worked extensively on the hypoxia signaling pathway and revealed its important role in the pathogenesis of different types of human cancers. Currently, we are investigating the role of the hypoxia pathway in glioma pathogenesis and malignancy and seeking potential therapeutic compounds and strategies based on targeting this pathway.
In addition to our work in hypoxic signaling in tumorigenesis, we have great experience and interest in glial biology and glial-derived neoplasms. To investigate the key molecules in glioma pathogenesis and aggressiveness, we analyzed clinical glioma specimens with different WHO grades and noticed differential expression of the embryonic gene, β-catenin, in a subset of gliomas. We further investigated the function of β-catenin in the normal brain and demonstrated that this protein is involved in brain cell repair under physiologic conditions. Furthermore, we showed that dysregulation of β-catenin could be important for glioma manifestation. Based on this hypothesis, we developed a glioma stem cell (GSC) model in our facility, which has become the latest cell line in studying GSCs in glioma research. By using this cutting edge cell model, we discovered that β-catenin, in addition to its role in normal wound healing, is important for GSC proliferation and self-renewal. This finding has opened a new page in brain tumor research and may lead to targeted drugs designed for glioma therapy. The findings that originated from this study have been published in PNAS and have garnered international attention. Due to our significant contribution to and credentials in glial biology and glioma research, we have been invited to compose a review article for Cellular and Molecular Life Science, to introduce topics related to major wound healing signaling pathways in glial cells and gliomas.
We also have extensive experience in mechanism studies and development of novel therapeutics for various central nervous system disorders, including Neurofibromatosis Type 2 (NF2) syndrome, Von Hippel-Lindau (VHL) syndrome, and Gaucher disease. In several original studies based on patient-derived specimens, we demonstrated that abnormalities in protein folding play important roles in disease phenotypes in these inherited disorders. We discovered that chaperones and co-chaperones, such as Hsp90, Cdc37, and Hsp27, are critical mediators in the pathogenic loss of key regulatory proteins in these disorders. Furthermore, we have collaborated with Lixte Biotechnology Holdings, Inc. (East Setauket, NY) to screen a series of small molecular compounds, from which we discovered that compounds inhibiting histone deacetylase (histone deacetylase inhibitors, HDACi) effectively elongate the lives of these proteins, and therefore correct the protein deficiencies observed in disease states. Moreover, we demonstrated that the pharmacologic mechanism of HDACi is through molecular chaperones, in which chaperone activity of Hsp90 and subsequent pre-mature endoplasmic reticulum-related protein degradation is inhibited. Currently, we are working on translating these discoveries into the development of new therapies targeting protein mis-folding, a novel therapeutic approach that is in contrast to the current standard-of-care of enzyme replacement, which can be both ineffective and extremely expensive for patients.
In summary, our research interests have focused and will continue to concentrate strongly upon central and peripheral nervous system disorders. Our work and publication record reflect our involvement across the major areas of human disease research, including the genetic basis for disease, proteomic changes in tumorigenesis, and development of novel therapeutic strategies to treat patients in the clinical setting.
Selected Key Publications
Targeting IDH1-Mutated Malignancies with NRF2 Blockade.JNCI. In Press: 2019. [ Journal Article ]
- N Engl J Med. 367(10): 922-930, 2012. [ Journal Article ]
β-Catenin signaling initiates the activation of astrocytes and its dysregulation contributes to the pathogenesis of astrocytomas.Proc Natl Acad Sci U S A. 109(18): 6963-6968, 2012. [ Journal Article ]
- Cancer Research. 77(7): 1709-1718, 2017. [ Journal Article ]
Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma.Clinical Cancer Research. 24: 3423-3432, 2018. [ Journal Article ]
|Yang Liu Ph.D.||Postdoctoral Fellow (Visiting)|
|Di Yu Ph.D.||Special Volunteer|
|Yiqiang Zhou Ph.D.||Postdoctoral Fellow (Visiting)|