> Detailanzeige

Limberger, Tanja; Schlederer, Michaela; Trachtová, Karolina; Garces de los Fayos Alonso, Ines; Yang, Jiaye; Högler, Sandra; Sternberg, Christina; Bystry, Vojtech; Oppelt, Jan; Tichý, Boris; Schmeidl, Margit; Kodajova, Petra; Jäger, Anton; Neubauer, Heidi A.; Oberhuber, Monika; Schmalzbauer, Belinda S.; Pospisilova, Sarka; Dolznig, Helmut; Wadsak, Wolfgang; Culig, Zoran; Turner, Suzanne D.; Egger, Gerda; Lagger, Sabine; Kenner, Lukas

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Literatur-
verwaltung

Zur
Merkliste

Lösche von
Merkliste

Per Whatsapp teilen

Schließen

Merkliste



Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
  • Medientyp: E-Artikel
  • Titel: KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
  • Beteiligte: Limberger, Tanja; Schlederer, Michaela; Trachtová, Karolina; Garces de los Fayos Alonso, Ines; Yang, Jiaye; Högler, Sandra; Sternberg, Christina; Bystry, Vojtech; Oppelt, Jan; Tichý, Boris; Schmeidl, Margit; Kodajova, Petra; Jäger, Anton; Neubauer, Heidi A.; Oberhuber, Monika; Schmalzbauer, Belinda S.; Pospisilova, Sarka; Dolznig, Helmut; Wadsak, Wolfgang; Culig, Zoran; Turner, Suzanne D.; Egger, Gerda; Lagger, Sabine; Kenner, Lukas
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Molecular Cancer
  • Sprache: Englisch
  • DOI: 10.1186/s12943-022-01542-8
  • ISSN: 1476-4598
  • Schlagwörter: Cancer Research ; Oncology ; Molecular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Frequent truncation mutations of the histone lysine N-methyltransferase <jats:italic>KMT2C</jats:italic> 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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>To investigate the functional effects of these mutations, we deleted the C-terminal catalytic core motif of <jats:italic>Kmt2c</jats:italic> specifically in mouse prostate epithelium. We analysed the effect of <jats:italic>Kmt2c</jats:italic> SET domain deletion in a <jats:italic>Pten</jats:italic>-deficient PCa mouse model in vivo and of truncation mutations of <jats:italic>KMT2C</jats:italic> in a large number of prostate cancer patients.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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<jats:italic>,</jats:italic> triggers loss of senescence, metastatic dissemination and dramatically reduces life expectancy. In <jats:italic>Kmt2c</jats:italic>-mutated tumours we show enrichment of proliferative MYC gene signatures and loss of expression of the cell cycle repressor p16<jats:sup>INK4A</jats:sup>. In addition, we observe a striking reduction in disease-free survival of patients with <jats:italic>KMT2C</jats:italic>-mutated prostate cancer.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>We identified truncating events of <jats:italic>KMT2C</jats:italic> 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 <jats:italic>KMT2C</jats:italic> 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.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang