Primary Faculty

Ralf Janknecht, Ph.D.

Ralf Janknecht, Ph.D.

Professor, Department of Cell Biology


Education:

Diplom, Biology and Chemistry, University of Bochum, Germany
Ph.D., Biochemistry, University of Bochum, Germany
Habilitation, Molecular Biology, Hannover Medical School, Germany

 


Contact Information:

Office Phone: (405) 271-8001  ext. 47420

 

Email: ralf-janknecht@ouhsc.edu

 

University of Oklahoma Health Sciences Center
975 NE 10th Street, 
Biomedical Research Center 1464
Oklahoma City, OK 73104, USA

 


Research Interests:

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 JMJD histone demethylases and protein hydroxylases as well as on the DNPH1 enzyme. Using a variety of in vitro and in vivo technologies, we strive to elucidate how these proteins modulate normal cell function and also contribute to the development and spread of tumors.

 

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 drives prostate tumorigenesis and its 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, some JMJD proteins are able to hydroxylate proteins or 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 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.

 

The DNPH1 Enzyme

We originally identified 2’-deoxynucleoside 5’-phosphate N-hydrolase 1 (DNPH1) as a downstream target gene of the HER2/Neu oncoprotein 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 discovered that DNPH1 can promote cancer formation, angiogenesis and metastasis.

Currently, we endeavor to determine the mechanisms by which DNPH1 affects tumorigenesis and also explore other potential functions of this enzyme. Another research direction is the identification of DNPH1 inhibitors and testing their utility as cancer drugs.

 

 


Selected Publications:

1.       Gu R, Kim TD, Song H, Sui Y, Shin S, Oh S, Janknecht R (2023). SET7/9-mediated methylation affects oncogenic functions of histone demethylase JMJD2A. JCI Insight 8, e164990.

2.       Gu R, Kim TD, Jiang H, Shin S, Oh S, Janknecht R (2023). Methylation of the epigenetic JMJD2D protein by SET7/9 promotes prostate tumorigenesis. Front Oncol 13, 1295613.

3.       Sui Y, Gu R, Janknecht R (2021). Crucial functions of the JMJD1/KDM3 epigenetic regulators in cancer. Mol Cancer Res 19, 3-13.

4.       Oh S, Song H, Freeman WM, Shin S, Janknecht R (2020). Cooperation between ETS transcription factor ETV1 and histone demethylase JMJD1A in colorectal cancer. Int J Oncol 57, 1319-1332.

5.       Sui Y, Li X, Oh S, Zhang B, Freeman WM, Shin S, Janknecht R (2020). Opposite roles of the JMJD1A interaction partners MDFI and MDFIC in colorectal cancer. Sci Rep 10, 8710.

6.       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.

7.       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, 406-418.

8.       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.

9.       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.

10.     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.

11.     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.

12.     Berry WL, Janknecht R (2013). KDM4/JMJD2 histone demethylases: Epigenetic regulators in cancer cells. Cancer Res 73, 2936-2942.

13.     Oh S, Janknecht R (2012). Histone demethylase JMJD5 is essential for embryonic development. Biochem Biophys Res Commun 420, 61-65.

14.     Kim TD, Shin S, Berry WL, Oh S, Janknecht R (2012). The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells. J Cell Biochem 113, 1368-1376.

 

List of all Publications:

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=janknecht+r

Google Scholar: https://scholar.google.com/citations?user=rnQO_ycAAAAJ&hl=en

 

Profile Last Updated: February 23, 2024