Uncontrolled cell growth within a tumor results in hypoxia as the metabolic needs of the cells exceed the ability of the tumor vasculature to provide oxygen and nutrients. In response to the hypoxic microenvironment, cells undergo a massive reprogramming of transcription to promote survival. The Hypoxia Inducible Transcription Factors (HIFs) are primary regulators of the hypoxic response and induce the expression of glycolytic genes, cell migration factors, and angiogenic factors. HIFs also induce expression of several transcriptional regulators, including several histone demethylases, providing a mechanism for the hypoxic cell to extend or fix the expression of pro-survival genes. One of these histone demethylases, JMJD2B, demethylates tri-methylated histone H3 lysine 9 (H3K9me3), a key marker of repressed chromatin structure. Hypoxic induction of JMJD2B may play an important role in activating gene expression to promote tumor growth. Consistent with this hypothesis, forced knock-down of JMJD2B expression reduces growth of tumor xenografts, and is overexpressed in ovarian cancers. In this proposal, the extent to which JMJD2B regulates tumor growth will be tested in vivo using tumor xenograft experiments and in vitro by assaying for cell proliferation, invasion, and angiogenesis as a result of JMJD2B expression (Specific Aim 1). Subsequent biochemical experiments will determine the mechanism of specific target gene regulation in hypoxia, identify new genes regulated by JMJD2B in hypoxia, and characterize the regulation of key pathways of genes important for the tumorigenic phenotype (Specific Aim 2). The experiments described in this proposal will establish the mechanisms utilized by JMJD2B to regulate tumorigenesis, while identifying new pathways to target for enhanced tumor therapies.

Public Health Relevance

Cancer cells typically grow faster than the surrounding blood vessels can supply oxygen and nutrients. In response to decreased oxygen (hypoxia), cancer cells alter their gene expression to enhance survival, resulting in more aggressive tumors. In this study we will determine the function of JMJD2B, a regulator of hypoxic gene expression in cancer cells, with the ultimate goal of finding better targets for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM104936-07
Application #
8534219
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$218,573
Indirect Cost
$73,823
Name
University of Kansas
Department
Type
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Lui, Asona; New, Jacob; Ogony, Joshua et al. (2016) Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells. BMC Cancer 16:487
Briley, Shawn M; Jasti, Susmita; McCracken, Jennifer M et al. (2016) Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction 152:245-60
Navakanitworakul, Raphatphorn; Hung, Wei-Ting; Gunewardena, Sumedha et al. (2016) Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles. Sci Rep 6:25486
Wilson, C; Qiu, L; Hong, Y et al. (2016) The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene :
Wang, Huizhen; Hastings, Richard; Miller, William L et al. (2016) Fshb-iCre mice are efficient and specific Cre deleters for the gonadotrope lineage. Mol Cell Endocrinol 419:124-38
Zhang, Zhen; Costa, Flávia C; Tan, Ee Phie et al. (2016) O-Linked N-Acetylglucosamine (O-GlcNAc) Transferase and O-GlcNAcase Interact with Mi2β Protein at the Aγ-Globin Promoter. J Biol Chem 291:15628-40
Belousov, Andrei B; Fontes, Joseph D (2016) Role of neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemic neuronal death. Neural Regen Res 11:75-6
Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Li, Yuan; McGreal, Steven; Zhao, Jean et al. (2016) A cell-based quantitative high-throughput image screening identified novel autophagy modulators. Pharmacol Res 110:35-49
Wilson, Nathan R; Olm-Shipman, Adam J; Acevedo, Diana S et al. (2016) SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination. Sci Rep 6:17735

Showing the most recent 10 out of 44 publications