Diplom, Biology and Chemistry, University of Bochum, Germany
Ph.D., Biochemistry, University of Bochum, Germany
Habilitation, Molecular Biology, Hannover Medical School, Germany
Office Phone: (405) 271-8001 ext. 47420
University of Oklahoma Health Sciences Center
975 NE 10th Street,
Biomedical Research Center 1464
Oklahoma City, OK 73104, USA
Our long-term objective is to understand how dysregulation of DNA-binding transcription factors, epigenetic regulators and metabolic enzymes leads to the initiation and progression of cancer and other illnesses, which may help to develop novel strategies of clinical treatment. In particular, we focus on the oncogenic transcription factor ETV1, the JMJD proteins, and the DNPH1 enzyme. Using a variety of in vitro and in vivo technologies, we endeavor to elucidate how these proteins modulate normal cell function and also contribute to the development of tumors and metabolic disorders.
The ETV1 transcription factor
ETS variant 1 (ETV1) belongs to the ETS class of DNA-binding transcription factors. Its activity is greatly stimulated by the RAF, RAS and HER2 oncoproteins through the induction of posttranslational modifications in ETV1. Moreover, chromosomal translocations involving ETV1 are found in prostate carcinomas and Ewing sarcomas, and mouse models overexpressing ETV1 develop prostatic intraepithelial neoplasia. Altogether, these data indicate that aberrant activation of ETV1 and subsequent dysregulation of its target genes are underlying causes of cancer. Indeed, we have identified several ETV1 target genes that are critical for cancer development. These include MMP7, a metalloproteinase that plays a role in tumor invasion and metastasis, and hTERT, the catalytic subunit of telomerase whose overexpression causes immortalization.
In the future, we would like to unravel the consequences of various posttranslational modifications for ETV1 function and examine how ETV1 alters gene expression programs to induce cancer.
The JMJD proteins
Jumonji C domain-containing (JMJD) proteins are implicated in chromatin regulation and often possess the ability to demethylate lysine residues on histones. Also, they are involved in developmental processes, and several JMJD proteins are suspected to be oncoproteins or tumor suppressors. We have initiated studies on many of the 33 known human JMJD proteins and already identified several seminal interaction partners. For instance, we found that JMJD2 proteins bind to and regulate androgen and estrogen receptors, the key villains in prostate or breast tumors. In addition, JMJD2A binds to and synergizes with ETV1 to drive prostate tumorigenesis and JMJD2A expression is correlated with the aggressiveness of the disease. These findings highlight that JMJD2A is a valid new target for therapeutic intervention.
Aside from demethylating histones, JMJD proteins have recently been found to hydroxylate proteins and to function as proteases. Moreover, it is now clear that quite a few JMJD proteins are localized within the cytoplasm, indicating roles for JMJD proteins beyond epigenetic regulation. Notably, several JMJD proteins are vastly understudied, but we have created corresponding knockout mouse models to unravel their physiological functions. Our preliminary analyses revealed phenotypes such as reduced cancer susceptibility, altered glucose tolerance, circadian rhythm and developmental defects.
Our goals are to analyze how JMJD proteins modulate chromatin structure, how they impact on cell physiology, which posttranslational modifications regulate their function, and how their knockout or overexpression in mice affects development, metabolism and neoplasia.
We originally identified 2’-deoxynucleoside 5’-phosphate N-hydrolase 1 (DNPH1) as a target gene of ETV1 in breast cancer. DNPH1 cleaves dNMPs into 2-deoxyribose 5-phosphate and free bases, but the physiological relevance of this enzymatic activity has remained unknown. Harnessing our DNPH1 knockout mice, we showed that DNPH1 can promote cancer formation, angiogenesis and metastasis.
Currently, we strive to determine the mechanisms by which DNPH1 affects tumorigenesis and also explore other potential functions of this enzyme. Another future endeavor will be to find inhibitors of DNPH1 and test their utility as cancer drugs.
Oh S, Shin S, Song H, Grande JP, Janknecht R (2019). Relationship between ETS transcription factor ETV1 and TGF-β-regulated SMAD proteins in prostate cancer. Sci Rep 9, 8186.
Oh S, Shin S, Janknecht R (2019). The small members of the JMJD protein family: Enzymatic jewels or jinxes? Biochim Biophys Acta – Rev Cancer 1871, 406-41.
Li X, Oh S, Song H, Shin S, Zhang B, Freeman WM, Janknecht R (2018). A potential common role of the Jumonji C domain-containing 1A histone demethylase and chromatin remodeler ATRX in promoting colon cancer. Oncol Lett 16, 6652-6662.
Li X, Moon G, Shin S, Zhang B, Janknecht R (2018). Cooperation between ETS variant 2 and Jumonji domain-containing 2 histone demethylases. Mol Med Rep 17, 5518-5527.
Kim TD, Oh S, Lightfoot SA, Shin S, Wren JD, Janknecht R (2016). Upregulation of PSMD10 caused by the JMJD2A histone demethylase. Int J Clin Exp Med 9, 10123-10134.
Kim TD, Shin S, Janknecht R (2016). ETS transcription factor ERG cooperates with histone demethylase KDM4A. Oncol Rep 35, 3679-3688.
Kim TD, Jin F, Shin S, Oh S, Lightfoot SA, Grande JP, Johnson AJ, van Deursen JM, Wren JD, Janknecht R (2016). Histone demethylase JMJD2A drives prostate tumorigenesis through transcription factor ETV1. J Clin Invest 126, 706-720.
Kim TD, Fuchs JR, Schwartz E, Abdelhamid D, Etter J, Berry WL, Li C, Ihnat MA, Li PK, Janknecht R (2014). Pro-growth role of the JMJD2C histone demethylase in HCT-116 colon cancer cells and identification of curcuminoids as JMJD2 inhibitors. Am J Transl Res 6, 236-247.
Berry WL, Kim TD, Janknecht R (2014). Stimulation of beta-catenin and colon cancer cell growth by the KDM4B histone demethylase. Int J Oncol 44, 1341-1348.
Oh S, Shin S, Lightfoot SA, Janknecht R (2013). 14-3-3 proteins modulate the ETS transcription factor ETV1 in prostate cancer. Cancer Res 73, 5110-5119.
Berry WL, Janknecht R (2013). KDM4/JMJD2 histone demethylases: Epigenetic regulators in cancer cells. Cancer Res 73, 2936-2942.
Shin S, Oh S, An S, Janknecht R (2013). ETS variant 1 regulates matrix metalloproteinase-7 transcription in LNCaP prostate cancer cells. Oncol Rep 29, 306-314.
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Google Scholar: https://scholar.google.com/citations?user=rnQO_ycAAAAJ&hl=en
Profile Last Updated: June 27, 2019