Titel (eng)

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Autor*in

Tanja Limberger   Medical University of Vienna / CBmed-Center for Biomarker Research in Medicine GmbH

Lukas Kenner   University of Veterinary Medicine Vienna / Medical University of Vienna / CBmed-Center for Biomarker Research in Medicine GmbH

Sabine Lagger   University of Veterinary Medicine Vienna

Gerda Egger   Medical University of Vienna / Ludwig Boltzmann Institute Applied Diagnostics

Suzanne D. Turner   Cambridge University / Masaryk University

Zoran Culig   Innsbruck Medical University

Wolfgang Wadsak   CBmed-Center for Biomarker Research in Medicine GmbH / Medical University of Vienna

Helmut Dolznig   Medical University of Vienna

Sarka Pospisilova   Masaryk University

Belinda S. Schmalzbauer   University of Veterinary Medicine Vienna

Monika Oberhuber   CBmed-Center for Biomarker Research in Medicine GmbH

Heidi A. Neubauer   University of Veterinary Medicine Vienna

Anton Jäger   Medical University of Vienna

Petra Kodajova   University of Veterinary Medicine Vienna

Margit Schmeidl   Medical University of Vienna

Boris Tichý   Masaryk University

Jan Oppelt   Masaryk University

Vojtech Bystry   Masaryk University

Christina Sternberg   University of Veterinary Medicine, Vienna / Medical University of Vienna

Sandra Högler   University of Veterinary Medicine Vienna

Jiaye Yang   Medical University of Vienna

Ines Garces de Los Fayos Alonso   University of Veterinary Medicine Vienna / Medical University of Vienna

Michaela Schlederer   Medical University of Vienna

Karolina Trachtová   Masaryk University / Medical University of Vienna

Verlag

BioMed Central

Beschreibung (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.

Sprache des Objekts

Englisch

Datum

2022

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Pten Loss; R/Bioconductor Package; Androgen Receptor; Mouse Model; Myc; Signature; Progression; Activation; Senescence; Overexpression

Mitglied in der/den Collection(s) (1)