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  • Z01
    • Backofen
    • Manke
  • Z02
    • Breit
    • Einsle
    • Günther
  • Z03 Central tasks

B01 The epigenetic regulator LSD1 controls tumourigenesis

Roland Schüle

Roland Schüle

Principal investigator of

The lysine specific demethylase 1 (LSD1) is a key regulator of androgen receptor (AR) function. We have explored the therapeutic potential of lysine-specific demethylase 1 (LSD1) in tumorigenesis. We unravelled that methylation of LSD1 by the histone methyltransferase G9a drives AR-dependent transcription and genomic integrity in prostate cancer. We will use our structural information to design and characterise chemical probes that inhibit binding of chromodomain-helicase-DNA binding protein 1 (CHD1) to methylated LSD1. The outcome of the project will pave way for novel avenues for therapeutic intervention with mechanistic insights.

Selected project-relevant publications

  • Metzger E., Wang S., Urban S., Willmann D., Schmidt A., Offermann A., Allen A., Sum M., Obier N., Cottard F., Ulferts S., Preca B.T., Hermann B., Maurer J., Greschik H., Hornung V., Einsle O., Perner S., Imhof A., Jung M. and Schule R. (2019) KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nat Struct Mol Biol 26, 361-371.
  • Barth J., Abou-El-Ardat K., Dalic D., Kurrle N., Maier A.M., Mohr S., Schutte J., Vassen L., Greve G., Schulz-Fincke J., Schmitt M., Tosic M., Metzger E., Bug G., Khandanpour C., Wagner S.A., Lubbert M., Jung M., Serve H., Schule R. and Berg T. (2019) LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML. Leukemia 33, 1411-1426.
  • Tosic M., Allen A., Willmann D., Lepper C., Kim J., Duteil D. and Schule R. (2018) Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells. Nat Commun 9, 366.
  • Metzger E., Stepputtis S.S., Strietz J., Preca B.T., Urban S., Willmann D., Allen A., Zenk F., Iovino N., Bronsert P., Proske A., Follo M., Boerries M., Stickeler E., Xu J., Wallace M.B., Stafford J.A., Kanouni T., Maurer J. and Schule R. (2017) KDM4 Inhibition Targets Breast Cancer Stem-like Cells. Cancer Res 77, 5900-591.
  • Greschik H., Duteil D., Messaddeq N., Willmann D., Arrigoni L., Sum M., Jung M., Metzger D., Manke T., Gunther T. and Schule R. (2017) The histone code reader Spin1 controls skeletal muscle development. Cell Death Dis 8, e3173.
  • Duteil D., Tosic M., Willmann D., Georgiadi A., Kanouni T. and Schule R. (2017) Lsd1 prevents age-programed loss of beige adipocytes. Proc Natl Acad Sci U S A 114, 5265-5270.
  • Greschik H., Schule R. and Gunther T. (2017) Selective targeting of epigenetic reader domains. Expert Opin Drug Discov 12, 449-463.
  • Castex J., Willmann D., Kanouni T., Arrigoni L., Li Y., Friedrich M., Schleicher M., Wohrle S., Pearson M., Kraut N., Meret M., Manke T., Metzger E., Schule R. and Gunther T. (2017) Inactivation of Lsd1 triggers senescence in trophoblast stem cells by induction of Sirt4. Cell Death Dis 8, e2631.
  • Duteil D., Tosic M., Lausecker F., Nenseth H.Z., Muller J.M., Urban S., Willmann D., Petroll K., Messaddeq N., Arrigoni L., Manke T., Kornfeld J.W., Bruning J.C., Zagoriy V., Meret M., Dengjel J., Kanouni T. and Schule R. (2016) Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue. Cell Rep 17, 1008-1021.
  • Slynko I., Schmidtkunz K., Rumpf T., Klaeger S., Heinzlmeir S., Najar A., Metzger E., Kuster B., Schule R., Jung M. and Sippl W. (2016) Identification of Highly Potent Protein Kinase C-Related Kinase 1 Inhibitors by Virtual Screening, Binding Free Energy Rescoring, and in vitro Testing. ChemMedChem doi: 10.1002/cmdc.201600284
  • Morera L., Roatsch M., Furst M.C., Hoffmann I., Senger J., Hau M., Franz H., Schule R., Heinrich M.R. and Jung M. (2016) 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. ChemMedChem doi: 10.1002/cmdc.201600218
  • Roatsch M., Robaa D., Pippel M., Nettleship J.E., Reddivari Y., Bird L.E., Hoffmann I., Franz H., Owens R.J., Schule R., Flaig R., Sippl W. and Jung M. (2016) Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases. Future Med Chem [epub ahead of print]
  • Metzger E., Willmann D., Mcmillan J., Forne I., Metzger P., Gerhardt S., Petroll K., Von Maessenhausen A., Urban S., Schott A.K., Espejo A., Eberlin A., Wohlwend D., Schule K.M., Schleicher M., Perner S., Bedford M.T., Jung M., Dengjel J., Flaig R., Imhof A., Einsle O. and Schule R. (2016) Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Nat Struct Mol Biol 23, 132-139.
  • Fedorov O., Castex J., Tallant C., Owen D.R., Martin S., Aldeghi M., Monteiro O., Filippakopoulos P., Picaud S., Trzupek J.D., Gerstenberger B.S., Bountra C., Willmann D., Wells C., Philpott M., Rogers C., Biggin P.C., Brennan P.E., Bunnage M.E., Schule R., Gunther T., Knapp S. and Muller S. (2015) Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. Sci Adv 1, e1500723
  • Ruger N., Roatsch M., Emmrich T., Franz H., Schule R., Jung M. and Link A. (2015) Tetrazolylhydrazides as Selective Fragment-Like Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. ChemMedChem 10, 1875-1883.
  • Kronig M., Walter M., Drendel V., Werner M., Jilg C.A., Richter A.S., Backofen R., Mcgarry D., Follo M., Schultze-Seemann W. and Schule R. (2015) Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity. Oncotarget 6, 1302-1314.
  • Franz H., Greschik H., Willmann D., Ozretic L., Jilg C.A., Wardelmann E., Jung M., Buettner R. and Schule R. (2015) The histone code reader SPIN1 controls RET signaling in liposarcoma. Oncotarget 6, 4773-4789.
  • Zhu D., Holz S., Metzger E., Pavlovic M., Jandausch A., Jilg C., Galgoczy P., Herz C., Moser M., Metzger D., Gunther T., Arnold S.J. and Schule R. (2014) Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells. Nat Commun 5, 3174.
  • Nam H.J., Boo K., Kim D., Han D.H., Choe H.K., Kim C.R., Sun W., Kim H., Kim K., Lee H., Metzger E., Schuele R., Yoo S.H., Takahashi J.S., Cho S., Son G.H. and Baek S.H. (2014) Phosphorylation of LSD1 by PKCalpha is crucial for circadian rhythmicity and phase resetting. Mol Cell 53, 791-805.
  • Ketscher A., Jilg C.A., Willmann D., Hummel B., Imhof A., Russeler V., Holz S., Metzger E., Muller J.M. and Schule R. (2014) LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. Oncogenesis 3, e120.
  • Jilg C.A., Ketscher A., Metzger E., Hummel B., Willmann D., Russeler V., Drendel V., Imhof A., Jung M., Franz H., Holz S., Kronig M., Muller J.M. and Schule R. (2014) PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells. Oncotarget 5, 12646-12664.
  • Duteil D., Metzger E., Willmann D., Karagianni P., Friedrichs N., Greschik H., Gunther T., Buettner R., Talianidis I., Metzger D. and Schule R. (2014) LSD1 promotes oxidative metabolism of white adipose tissue. Nat Commun 5, 4093.