KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F22%3A00126463" target="_blank" >RIV/00216224:14740/22:00126463 - isvavai.cz</a>
Result on the web
<a href="https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01542-8" target="_blank" >https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01542-8</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1186/s12943-022-01542-8" target="_blank" >10.1186/s12943-022-01542-8</a>
Alternative languages
Result language
angličtina
Original language name
KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
Original language 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/LM2018132" target="_blank" >LM2018132: The National Center for Medical Genomic</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Molecular Cancer
ISSN
1476-4598
e-ISSN
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Volume of the periodical
21
Issue of the periodical within the volume
1
Country of publishing house
GB - UNITED KINGDOM
Number of pages
19
Pages from-to
89
UT code for WoS article
000776200300001
EID of the result in the Scopus database
2-s2.0-85127261335