Zhong Yun PhD
Associate Professor of Therapeutic Radiology
Research Interests
Molecular and cancer biology; Stem cell biology, hypoxia; microRNA, tumor microenvironment; Obesity and metabolic syndromes
Research Summary
My lab focuses on two main areas of research with a goal to provide pertinent insights for the mechanistic understanding of human diseases. First, we are trying to understand the mechanisms by which stem cell maintenance and differentiation are regulated by environmental factors such as oxygen or by epigenetic mechanisms involving microRNAs. We are particularly interested in regulation of cancer stem cell functions. The second area of our research concerns the role of oxygen-sensing pathway in the regulation of energy homeostasis, in the pathological progression of obesity, and in obesity-associated metabolic syndromes including type 2 diabetes and cardiovascular diseases.
Extensive Research Description
Oxygen is essential to all aerobic life forms on earth. In addition to its role in energy
metabolism, oxygen has broad biological impact from embryogenesis to
adulthood. This notion is strongly
supported by the fact that mammalian embryos develop in a low oxygen or hypoxic
environment (approximately 3% O2 or less) during the first trimester. Furthermore, recent studies from us and
other laboratories have shown that oxygen can directly regulate the
differentiation of stem/precursor cells, and may participate in the maintenance
of stem cells in the stem cell niche.
Our overall research interest is to investigate the
mechanisms by which tissue microenvironment, especially hypoxia, regulates the
important biological processes including cellular differentiation, metabolism,
tumor progression and tumor response to therapy. Our current focuses are (1) the role of hypoxia in the
regulation of stem cell maintenance and differentiation, (2) the effects of
hypoxia on cancer cell differentiation, malignant progression and response to
therapy, (3) the role of HIF pathway in adipocytes and myocytes, especially in
the regulation of energy homeostasis, and the pathogenesis of obesity and/or
type 2 diabetes.
The oxygen-sensing pathway and regulation of cancer stem
cell functions.
Nearly all of solid tumors contain areas of hypoxia. Tumor hypoxia is strongly correlated
with advanced disease stage and poor clinical outcome. Increasing amounts of evidence suggest
that hypoxic tumor cells tend to be poorly differentiated. We hypothesize that hypoxia inhibits
cancer cell differentiation and thus arrests tumor cells in their
undifferentiated state, which represents a novel approach to the understanding
of tumor progression under hypoxic conditions. Poorly differentiated tumor cells are almost always more
tumorigenic and more malignant than their more differentiated
counterparts. The extensive
proliferative potentials and long lifespan will allow the undifferentiated
tumor cells to accumulate stable genetic and epigenetic changes that eventually
confer the malignant phenotype.
Therefore, hypoxia-mediated differentiation arrest of tumorigenic cells
provides a platform that allows continuous accumulation and perpetuation of
both genetic and epigenetic changes that result in tumor malignancy. Currently, we are using several tumor
model systems to test this hypothesis.
These studies will have the potentials to provide new approaches toward
effective therapy for solid tumors, e.g. by specifically targeting the
undifferentiated cancer stem cell population in the hypoxic regions.
The oxygen-sensing pathway and metabolism: Implications
in obesity and diabetes.
Obesity has become a world wide epidemic and is associated with more than 30
human diseases including type 2 diabetes, cardiovascular disease, and
cancer. Adipose tissue plays a
critical role in the development of obesity and other metabolic syndromes. It has been shown that
obesity results in adipose tissue hypoxia, suggesting that the oxygen-sensing
pathway would play a key role in the pathological progression of obesity and
its related diseases.
We were the first to investigate the mechanisms by which HIF-1
regulates the adipogenic differentiation.
We have found that HIF-1 is both necessary and sufficient to inhibit the
adipogenic differentiation of preadipocytes. Furthermore, hypoxia arrests preadipocytes in their
stem/precursor state. We have
generated a genetic mouse model to test the hypothesis that HIF plays an
important role in the development and functions of adipose tissue, as well as
in the pathogenesis of obesity and related metabolic syndromes including
diabetes and cardiovascular diseases.
Selected Publications
- Kim, Y., Lin, Q., Zelterman, D., and Yun, Z. (2009) Hypoxia-Regulated Delta-Like 1 Homolog Enhances Cancer Stemness and Tumorigenicity. Cancer Res. 69:9271-80, PMID: 19934310.
- Kim Y, Lin Q, Glazer PM, Yun Z. Hypoxic tumor microenvironment and cancer cell differentiation. Curr Mol Med. 2009 May9(4):425-34.
- Lin Q, Gao Z, Alarcon RM, Ye J, Yun Z. A role of miR-27 in the regulation of adipogenesis. FEBS J. 2009 Apr276(8):2348-58.
- Lin Q, Lee YJ, Yun Z. Differentiation arrest by hypoxia. J Biol Chem. 2006 Oct 13281(41):30678-83. Epub 2006 Aug 22.
- Yun, Z.*, Lin, Q., and Giaccia, A.J.* (2005) Adaptive Myogenesis under Hypoxia. Mol. Cell Biol. 25:3040-55, PMID: 15798192.
- Yun, Z., Maecker, H. L., Johnson, R. S. and Giaccia, A. J. (2002) Inhibition of PPAR?2 Gene Expression by the HIF-1 Regulated Gene DEC1/Stra13: A Mechanism for Regulation of Adipogenesis by Hypoxia. Developmental Cell 2:331-41, PMID: 11879638.
- Maecker, H. L., Yun, Z.; Maecker, H. T., and Giaccia, A. J. (2002) Epigenetic Changes in Tumor Fas Levels Determine Immune Escape and Response to Therapy. Cancer Cell. 2:139-48, PMID: 12204534.
