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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Kansas City
United States
Zip Code
Tran, Pamela V; Sharma, Madhulika; Li, Xiaogang et al. (2014) Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 102:159-73
Cha, Jeeyeon; Bartos, Amanda; Park, Craig et al. (2014) Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Rep 8:382-92
Pierce, A N; Ryals, J M; Wang, R et al. (2014) Vaginal hypersensitivity and hypothalamic-pituitary-adrenal axis dysfunction as a result of neonatal maternal separation in female mice. Neuroscience 263:216-30
Kumar, T Rajendra (2014) The quest for male germline stem cell markers: PAX7 gets ID'd. J Clin Invest 124:4219-22
Rumi, M A Karim; Dhakal, Pramod; Kubota, Kaiyu et al. (2014) Generation of Esr1-knockout rats using zinc finger nuclease-mediated genome editing. Endocrinology 155:1991-9
Tan, Ee Phie; Villar, Maria T; E, Lezi et al. (2014) Altering O-linked ?-N-acetylglucosamine cycling disrupts mitochondrial function. J Biol Chem 289:14719-30
Saadi, Irfan; Das, Pragnya; Zhao, Minglian et al. (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development 140:2697-702
Dasouki, Majed J; Rafi, Syed K; Olm-Shipman, Adam J et al. (2013) Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 122:3440-9
Taniguchi, Cullen M; Finger, Elizabeth C; Krieg, Adam J et al. (2013) Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med 19:1325-30
Abrahamson, Dale R; St John, Patricia L; Stroganova, Larysa et al. (2013) Laminin and type IV collagen isoform substitutions occur in temporally and spatially distinct patterns in developing kidney glomerular basement membranes. J Histochem Cytochem 61:706-18

Showing the most recent 10 out of 11 publications