KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

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Authors	LIMBERGER Tanja SCHLEDERER Michaela TRACHTOVÁ Karolína ALONSO Ines Garces de los Fayos YANG Jiaye HOEGLER Sandra STERNBERG Christina BYSTRÝ Vojtěch OPPELT Jan TICHÝ Boris SCHMEIDL Margit KODAJOVA Petra JAEGER Anton NEUBAUER Heidi A OBERHUBER Monika SCHMALZBAUER Belinda S POSPÍŠILOVÁ Šárka DOLZNIG Helmut WADSAK Wolfgang CULIG Zoran TURNER Suzanne Dawn EGGER Gerda LAGGER Sabine KENNER Lukas
Year of publication	2022
Type	Article in Periodical
Magazine / Source	Molecular Cancer
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01542-8
Doi	http://dx.doi.org/10.1186/s12943-022-01542-8
Keywords	Prostate cancer; Senescence; Metastasis; KMT2C; MYC; p16(INK4A)
Description	Background 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. Methods 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. Results 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 p16(INK4A). In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer. Conclusions 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.
Related projects:	National Center for Medical Genomics