Roland Schüle

University Medical Center Freiburg

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Eric Metzger

University Medical Center Freiburg

Manfred Jung

University of Freiburg

Dominica Willmann

University Medical Center Freiburg

Reinhard Buettner

University of Cologne

Wolfgang Sippl

Martin Luther University Halle-Wittenberg

Sylvia Urban

RMIT University

Jutta Kirfel

University Hospital Schleswig-Holstein

Holger Greschik

University Medical Center Freiburg

Thomas Günther

Leibniz Institute of Virology (LIV)

Judith M. Müller

University Medical Center Freiburg

Cooperative Institutions

University of Freiburg

256

Heidelberg University

147

University Medical Center Freiburg

138

German Cancer Research Center

111

Centre National de la Recherche Scientifique

Inserm

Deutschen Konsortium für Translationale Krebsforschung

Goethe University Frankfurt

University of Oxford

Friedrich-Alexander-Universität Erlangen-Nürnberg

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

The Clinically Used Iron Chelator Deferasirox is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

Manfred Jung Martin Roatsch Inga Hoffmann Martine I. Abboud Rebecca L. Hancock

Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are epigenetic eraser enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of action investigations revealed that one compound, deferasirox, is a bona fide active site-binding inhibitor as shown by kinetic and spectroscopic studies. Synthesis of derivatives with improved cell permeability resulted in significant upregulation of histone trimethylation and potent cancer cell growth inhibition. Deferasirox was also found to similarly inhibit human 2OG-dependent hypoxia inducible factor prolyl hydroxylase activity. Therapeutic effects of clinically used deferasirox may thus involve transcriptional regulation through 2OG oxygenase inhibition. Deferasirox may provide a useful starting point for the development of novel anticancer drugs targeting 2OG oxygenases and a valuable tool compound for investigations of KDM function.

Deferasirox

10.26434/chemrxiv.7699853.v1

Cite

Citations (0)

A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2

The Journal of Experimental Medicine (2012)

Kai Kaufmann Albert Gründer Tobias Hadlich Julius Wehrle Monika Gothwal

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase inhibitor (HDAC-I) vorinostat restored physiological levels of histone H3 acetylation, decreased NF-E2 expression, and normalized platelet numbers. Similarly, MPN patients treated with an HDAC-I exhibited a decrease in NF-E2 expression. These data establish a role for NF-E2 in the pathophysiology of MPNs and provide a molecular rationale for investigating epigenetic alterations as novel targets for rationally designed MPN therapies.

Vorinostat

Histone deacetylase inhibitor

Myelopoiesis

10.1084/jem.20110540

Cite

Citations (71)

Supplementary Materials and Methods from KMT9 Controls Stemness and Growth of Colorectal Cancer

Christopher Berlin Félicie Cottard Dominica Willmann Sylvia Urban Stephan M. Tirier

<p>File with all the Supplementary Materials and Methods</p>

10.1158/0008-5472.22430692.v1

Cite

Citations (0)

L-shell ionization probability of Pb by 2-, 3-, 6-MeV protons

Physical review. A, General physics (1976)

K. E. Stiebing H. T. Schmidt Roland Schüle Κ. Bethge I. Tserruya

The impact-parameter dependences of $L\ensuremath{\alpha}$, $L\ensuremath{\beta}$, and total $L$-shell x-ray production of Pb by 2-, 3-, and 6-MeV proton bombardment have been measured and compared with theoretical calculations based on the semiclassical approximation (SCA) and the binary-encounter approximation (BEA). The SCA satisfactorily reproduces the details of the ionization probabilities but overestimates the results at large impact parameters. The BEA does not predict the appropriate structure observed in the x-ray production probabilities. The BEA results are too low at small impact parameters, but in good agreement with measured values at large impact parameters. The behavior at large impact parameters explains the failure of the SCA in predicting the $L$-shell x-ray production total cross sections (the calculated values are too high), whereas the BEA cross sections are in close agreement with experiment.

Semiclassical physics

Impact parameter

10.1103/physreva.14.146

Cite

Citations (16)

Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases

Future Medicinal Chemistry (2016)

Martin Roatsch Dina Robaa Martin Pippel Joanne E. Nettleship Yamini Reddivari

Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition.Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3.Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.

Demethylase

Tripeptide

10.4155/fmc.15.188

Cite

Citations (16)

LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6

Oncogenesis (2014)

Anett Ketscher Cordula A. Jilg Dominica Willmann Barbara Hummel Axel Imhof

Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.

Paxillin

10.1038/oncsis.2014.34

Cite

Citations (62)

Lsd1 prevents age-programed loss of beige adipocytes

Proceedings of the National Academy of Sciences (2017)

Delphine Duteil Milica Tošić Dominica Willmann Anastasia Georgiadi Toufike Kanouni

Significance Over time, beige adipocytes gain a white adipocyte morphology and lose their thermogenic activity. Here we show that levels of the epigenetic eraser lysine-specific demethylase 1 (Lsd1) decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Maintaining adipocyte-specific expression of Lsd1 in transgenic mice preserves the pool of beige adipocytes in old mice. Vice versa, using GFP reporter mice, we traced the fate of beige adipocytes and showed that adipocyte-specific loss of Lsd1 results in a premature beige-to-white adipocyte transition in vivo. Maintenance of beige adipocytes is mediated by the Lsd1 target gene peroxisome proliferator-activated receptor α (Ppara) and pharmacological activation of Ppara rescues the loss of beige adipocytes in Lsd1-KO mice. Together, we identified Lsd1 as a regulator of beige adipocyte maintenance.

Demethylase

10.1073/pnas.1702641114

Cite

Citations (45)

Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells

Nature Communications (2014)

Dongmei Zhu Stefanie Hölz Eric Metzger Mihael Pavlovic Anett Jandausch

Trophoblast

Demethylase

10.1038/ncomms4174

Cite

Citations (59)

Tofacitinib and analogs as inhibitors of the histone kinase PRK1 (PKN1)

Future Medicinal Chemistry (2016)

Dmytro Ostrovskyi Tobias Rumpf Julia Eib Alexandre Lumbroso Inna Slynko

The histone kinase PRK1 has been identified as a potential target to combat prostate cancer but selective PRK1 inhibitors are lacking. The US FDA -approved JAK1-3 inhibitor tofacitinib also potently inhibits PRK1 in vitro.We show that tofacitinib also inhibits PRK1 in a cellular setting. Using tofacitinib as a starting point for structure-activity relationship studies, we identified a more potent and another more selective PRK1 inhibitor compared with tofacitinib. Furthermore, we found two potential PRK1/JAK3-selectivity hotspots.The identified inhibitors and the selectivity hotspots lay the basis for the development of selective PRK1 inhibitors. The identification of PRK1, but also of other cellular tofacitinib targets, has implications on its clinical use and on future development of tofacitinib-like JAK inhibitors. [Formula: see text].

10.4155/fmc-2016-0132

Cite

Citations (11)

Supplementary Figures 1-4 from Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy

Johannes H. Schulte Soyoung Lim Alexander Schramm Nicolaus Friedrichs Jan Köster

Supplementary Figures 1-4 from Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy

Demethylase

10.1158/0008-5472.22381047.v1

Cite

Citations (0)