https://phaidra.vetmeduni.ac.at/o:1878 KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis Limberger, Tanja Tanja Limberger Medical University of Vienna / CBmed-Center for Biomarker Research in Medicine GmbH Kenner, Lukas Lukas Kenner 0000-0003-2184-1338 University of Veterinary Medicine Vienna / Medical University of Vienna / CBmed-Center for Biomarker Research in Medicine GmbH Lagger, Sabine Sabine Lagger 0000-0002-3032-9910 University of Veterinary Medicine Vienna Egger, Gerda Gerda Egger Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics Turner, Suzanne D. Suzanne D. Turner Cambridge University / Masaryk University Culig, Zoran Zoran Culig Innsbruck Medical University Wadsak, Wolfgang Wolfgang Wadsak CBmed-Center for Biomarker Research in Medicine GmbH / Medical University of Vienna Dolznig, Helmut Helmut Dolznig Medical University of Vienna Pospisilova, Sarka Sarka Pospisilova Masaryk University Schmalzbauer, Belinda S. Belinda S. Schmalzbauer 0000-0002-1881-0883 University of Veterinary Medicine Vienna Oberhuber, Monika Monika Oberhuber CBmed-Center for Biomarker Research in Medicine GmbH Neubauer, Heidi A. Heidi A. Neubauer 0000-0001-7372-7786 University of Veterinary Medicine Vienna Jäger, Anton Anton Jäger Medical University of Vienna Kodajova, Petra Petra Kodajova University of Veterinary Medicine Vienna Schmeidl, Margit Margit Schmeidl Medical University of Vienna Tichý, Boris Boris Tichý Masaryk University Oppelt, Jan Jan Oppelt Masaryk University Bystry, Vojtech Vojtech Bystry Masaryk University Sternberg, Christina Christina Sternberg University of Veterinary Medicine, Vienna / Medical University of Vienna Högler, Sandra Sandra Högler 0000-0002-6899-5273 University of Veterinary Medicine Vienna Yang, Jiaye Jiaye Yang Medical University of Vienna Garces de Los Fayos Alonso, Ines Ines Garces de Los Fayos Alonso 0000-0002-0187-4194 University of Veterinary Medicine Vienna / Medical University of Vienna Schlederer, Michaela Michaela Schlederer Medical University of Vienna Trachtová, Karolina Karolina Trachtová Masaryk University / Medical University of Vienna BioMed Central text eng Frequent truncation mutations of the histone lysine N-methyltransferase KMT2C have been detected by whole exome sequencing studies in various cancers, including malignancies of the prostate. However, the biological consequences of these alterations in prostate cancer have not yet been elucidated.To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of Kmt2c specifically in mouse prostate epithelium. We analysed the effect of Kmt2c SET domain deletion in a Pten-deficient PCa mouse model in vivo and of truncation mutations of KMT2C in a large number of prostate cancer patients.We show here for the first time that impaired KMT2C methyltransferase activity drives proliferation and PIN formation and, when combined with loss of the tumour suppressor PTEN, triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In Kmt2c-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer.We identified truncating events of KMT2C as drivers of proliferation and PIN formation. Loss of PTEN and KMT2C in prostate cancer results in loss of senescence, metastatic dissemination and reduced life expectancy. Our data demonstrate the prognostic significance of KMT2C mutation status in prostate cancer patients. Inhibition of the MYC signalling axis may be a viable treatment option for patients with KMT2C truncations and therefore poor prognosis. Pten Loss; R/Bioconductor Package; Androgen Receptor; Mouse Model; Myc; Signature; Progression; Activation; Senescence; Overexpression http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:1878/download 10.1186/s12943-022-01542-8 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Molecular Cancer 21(1) (2022) Molecular Cancer 21 1 3.11 MB 2022