Control of histone demethylase activity: An innovative therapeutic concept to fight hormone refractory prostate cancer
Final Report Abstract
Carcinoma of the prostate is the second leading cause of cancer related deaths in men in the Western hemisphere. Despite important advances in current androgen deprivation therapy a significant number of patients develop castration resistant prostate cancer and rapidly progress to metastatic disease. Due to current lack of treatment options their disease is final. Thus, the major challenge remains to identify effective therapeutic concepts to fight prostate cancer. Modulating the activities of epigenetic enzymes such as the histone demethylase LSD1 and/or demethylase controlling signalling proteins such as the kinase PRK1 is a therapeutic concept to block tumour growth. Since this strategy is not targeting androgen receptor (AR) directly but rather blocks androgen receptor function by inhibiting the activity of AR-associated epigenetic proteins. Thus, this therapeutic concept potentially preserves the tumour to develop hormone resistance. To verify the concept, we validated in this Reinhart Koselleck-Projekt PRK1 and LSD1 as targets of pharmacological intervention that governs prostate cancer evolution. LSD1 is a major regulator of AR-controlled transcription and genomic integrity. We identified signalling mechanisms that regulate LSD1 function and small molecule inhibitors that block the enzymatic activity of LSD1. Thus, our data paved the way for the intense development of LSD1 inhibitors by pharmaceutical companies, which are currently tested in seven clinical phase I/II studies. Our genetically-modified LSD1 mouse models (knock-out, knock-in, and transgenic mice) provided not only the basis for the validation of these LSD1 inhibitors in vivo, but also uncovered key physiological functions of LSD1 in stem cells maintenance, adipogenesis, myogenesis, and aging. Taken together, this Reinhart Koselleck-Projekt allowed me to identify and analyse basic epigenetic mechanisms, to test them in cellular and animal models of disease and to explore the potential of epigenetic regulators as suitable targets for pharmacological intervention. Clearly, the future impact of this work will deliver novel insights into epigenetic pathways and mechanisms in a variety of disease indications and ultimately will provide novel therapeutic targets and concepts, epigenetic biomarkers and chemical probes that interfere with epigenetic pathways and have the potential as starting points for the development as therapeutic interventions. Finally, and of utmost importance, due to the visionary scope of the proposal, this work would have been impossible without the scientific and financial freedom provided by the Reinhart Koselleck-Projekt.
Publications
- (2013) Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity. J Med Chem. 56, 7334-7342
Schmitt, M.L., Hauser, A.T., Carlino, L., Pippel, M., Schulz-Fincke, J., Metzger, E., Willmann, D., Yiu, T., Barton, M., Schüle, R., Sippl, W. and Jung, M.
(See online at https://doi.org/10.1021/jm400792m) - (2014) CtBP and associated LSD1 are required for transcriptional activation by NeuroD1 in gastrointestinal endocrine cells. Mol Cell Biol. 34, 2308-2317
Ray SK, Li HJ, Metzger M, Schüle R. and Leiter AB
(See online at https://doi.org/10.1128/MCB.01600-13) - (2014) Heterogeneous antibody based activity assay for lysine specific demethylase 1 (LSD1) on a histone peptide substrate. J. Biomol. Screen 19, 973-978
Schmitt, M.L., Ladwein, K.I., Carlino, L., Schulz-Fincke, J., Willmann, D., Metzger, E., Schilcher, P., Imhof, A., Schüle, R., Sippl, W. and Jung, M.
(See online at https://doi.org/10.1177/1087057114529156) - (2014) LSD1 controls metastasis of androgen-independent prostate cancer cells through PXN and LPAR6. Oncogenesis 3, e120
Ketscher, A., Jilg, CA., Willmann, D., Hummel, B., Imhof, A., Rüsseler, V., Hölz, S., Müller, JM., Metzger, E. and Schüle, R.
(See online at https://doi.org/10.1038/oncsis.2014.34) - (2014) LSD1 promotes oxidative metabolism of white adipose tissue. Nat. Commun. 5, 4093
Duteil, D., Metzger,E., Willmann, D., Karagianni, P., Friedrichs, N., Greschik, H., Günther,T., Buettner, R., Talianidis, I., Metzger, D. and Schüle, R.
(See online at https://doi.org/10.1038/ncomms5093) - (2014) Lsd1 regulates differentiation onset and migration of trophoblast stem cells. Nat. Commun. 5, 3174-3184
Zhu, D., Hölz, S., Metzger, E., Pavlovic, M., Jandausch, A., Jilg, C., Galgoczy, P., Herz, C., Moser, M., Metzger, D., Günther, T., Arnold, S.J. and Schüle, R.
(See online at https://doi.org/10.1038/ncomms4174) - (2014) Lysine Specific Demethylase 1 has Dual Functions as a Major Regulator of Androgen Receptor Transcriptional Activity. Cell Rep. 9, 1618-1627
Cai, C., He, H.H., Gao, S., Chen, S., Yu, Z., Gao, Y., Chen, S., Chen, M.W., Zhang, J., Ahmed. A., Wang, Y., Metzger, E., Schüle, R., X. Liu, X.S., Brown, M. and Balk, S.P.
(See online at https://doi.org/10.1016/j.celrep.2014.11.008) - (2014) Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting. Mol. Cell 53, 791-805
Nam, H.J., Boo, K., Kim, D.H., Choe, H.K., Kim, C.R., Sun, W., Kim, H., Kim, K., Lee, H., Schüle, R., Yoo, S-H., Takahashi, J.S., Cho, S., Son, G.H. and Baek, S.H.
(See online at https://doi.org/10.1016/j.molcel.2014.01.028) - (2014) PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells. Oncotarget 5, 12646-12664
Jilg, C.A., Ketscher, A., Metzger, E., Hummel, B., Willmann, D., Rüsseler, V., Drendel, V., Imhof, A., Jung, M., Franz, H., Hölz, H., Krönig, M., Judith M. Müller, J.M. and Schüle, R.
(See online at https://doi.org/10.18632/oncotarget.2653) - (2014) Virtual Screening of PRK1 Inhibitors: Ensemble Docking, RescoringUsing Binding Free Energy Calculation and QSAR Model Development. J. Chem. Inf. Model 54, 138-150
Slynko, I., Scharfe, M., Rumpf, T., Eib, J., Metzger, E., Schüle, R., Jung, M. and Sippl, W.
(See online at https://doi.org/10.1021/ci400628q) - (2015) Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity. Oncotarget 6, 1302-1314
Krönig, M., Walter, M., Drendel, V., Werner, M., Jilg, C.A., Richter, A.S., Backofen, R., McGarry, D., Follo, M., Schultze-Seemann, W. and Schüle, R.
(See online at https://dx.doi.org/10.18632%2Foncotarget.2744) - (2015) The histone code reader SPIN1 controls RET signaling in liposarcoma. Oncotarget 6, 4773-4489
Franz, H., Greschik, H., Willmann, D., Ozretić, L., Jilg, C.A., Wardelmann, E., Jung, M., Buettner, R. and Schüle, R.
(See online at https://doi.org/10.18632/oncotarget.3000) - (2016) Assembly of methylated KDM1 and CHD1 drives AR-dependent transcription and translocation. Nat. Struct. Mol. Biol. 23, 132-139
Metzger, E., Willmann, D., McMillan, J., Forne, I., Petroll, K., Metzger, P., Gerhardt, S., Maessenhausen, A., Schott, A-K., Espejo, A., Eberlin, A., Wohlwend, D., Schüle, K.M., Schleicher, M., Perner, S., Bedford, M.T., Jung, M., Dengjel, J., Flaig, R., Imhof, A., Einsle, O. and Schüle, R.
(See online at https://doi.org/10.1038/nsmb.3153) - (2016) Identification of a small-molecule ligand of the epigenetic reader protein Spindlin1 via a versatile screening platform. Nucleic Acids Res
Wagner, T., Greschik, H., Burgahn, T., Schmidtkunz, K., Schott, A.K., McMillan, J., Baranauskiene, L., Yan, X., Fedorov, O., Jian, J., Oppermann, U., Matulis, D., Schüle, R. and Jung, M.
(See online at https://doi.org/10.1093/nar/gkw089) - (2016) Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation. eLIFE
Ancelin, K., Syx, L., Borensztein, M., Ranisavljevic, N., Vassilev, I., Briseno-Roa, L., Liu, T., Metzger, E., Servant, N., Barillot, E., Chen, C-J., Schüle, R. and Heard, E.
(See online at https://doi.org/10.7554/eLife.08851)
