Characterisation of the lysine methyltransferases KMT9 and KMT10

B01

Project Summary

We have identified the novel histone methyltransferase KMT9 and depletion of this enzyme severely affects proliferation of prostate cancer cells and prostate tumours. Our findings provide a promising novel paradigm for the treatment of castration-resistant prostate cancer. We developed drug-like inhibitors with high potency and selectivity. We propose to evaluate the therapeutic potential of KMT9 inhibitors and their impact on physiology and pathology and to characterise enzymatic inactive KMT9α knock-in mice. Furthermore, we will characterise the novel histone methyltransferase KMT10.

Selected project-relevant publications

  • Frew I.J., Timmers H.T.M., Schüle R. and Gratzke C. (2020) The complex genetics of epigenetics in urothelial carcinomas. Nat Rev Urol, doi: 10.1038/s41585-41020-00386-41585.
  • Baumert H.M., Metzger E., Fahrner M., George J., Thomas R.K., Schilling O. and Schüle R. (2020) Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death. Cancer Cell Int 20, 52.
  • 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.
  • 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.
  • 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.
  • 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.