KMT2C methyltransferase domain regulated INK4A expression
suppresses prostate cancer metastasis

J 2022

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

LIMBERGER, Tanja, Michaela SCHLEDERER, Karolína TRACHTOVÁ, Ines Garces de los Fayos ALONSO, Jiaye YANG et. al.

Basic information

Original name

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Authors

LIMBERGER, Tanja, Michaela SCHLEDERER, Karolína TRACHTOVÁ (203 Czech Republic, belonging to the institution), Ines Garces de los Fayos ALONSO, Jiaye YANG, Sandra HOEGLER, Christina STERNBERG, Vojtěch BYSTRÝ (203 Czech Republic, belonging to the institution), Jan OPPELT (203 Czech Republic, belonging to the institution), Boris TICHÝ (203 Czech Republic, belonging to the institution), Margit SCHMEIDL, Petra KODAJOVA, Anton JAEGER, Heidi A NEUBAUER, Monika OBERHUBER, Belinda S SCHMALZBAUER, Šárka POSPÍŠILOVÁ (203 Czech Republic, guarantor, belonging to the institution), Helmut DOLZNIG, Wolfgang WADSAK, Zoran CULIG, Suzanne Dawn TURNER (826 United Kingdom of Great Britain and Northern Ireland, belonging to the institution), Gerda EGGER, Sabine LAGGER and Lukas KENNER

Edition

Molecular Cancer, LONDON, BioMed Central, 2022, 1476-4598

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 37.300

RIV identification code

RIV/00216224:14740/22:00126463

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1186/s12943-022-01542-8

UT WoS

000776200300001

Keywords in English

Prostate cancer; Senescence; Metastasis; KMT2C; MYC; p16(INK4A)

Abstract

V originále

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.

Links

90132, large research infrastructures

Name: NCMG II

Citovat

LIMBERGER, Tanja, Michaela SCHLEDERER, Karolína TRACHTOVÁ, Ines Garces de los Fayos ALONSO, Jiaye YANG, Sandra HOEGLER, Christina STERNBERG, Vojtěch BYSTRÝ, Jan OPPELT, Boris TICHÝ, Margit SCHMEIDL, Petra KODAJOVA, Anton JAEGER, Heidi A NEUBAUER, Monika OBERHUBER, Belinda S SCHMALZBAUER, Šárka POSPÍŠILOVÁ, Helmut DOLZNIG, Wolfgang WADSAK, Zoran CULIG, Suzanne Dawn TURNER, Gerda EGGER, Sabine LAGGER and Lukas KENNER. KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis. Molecular Cancer. LONDON: BioMed Central, 2022, vol. 21, No 1, p. 89-107. ISSN 1476-4598. Available from: https://dx.doi.org/10.1186/s12943-022-01542-8.

@article{2212060,
   author = {Limberger, Tanja and Schlederer, Michaela and Trachtová, Karolína and Alonso, Ines Garces de los Fayos and Yang, Jiaye and Hoegler, Sandra and Sternberg, Christina and Bystrý, Vojtěch and Oppelt, Jan and Tichý, Boris and Schmeidl, Margit and Kodajova, Petra and Jaeger, Anton and Neubauer, Heidi A and Oberhuber, Monika and Schmalzbauer, Belinda S and Pospíšilová, Šárka and Dolznig, Helmut and Wadsak, Wolfgang and Culig, Zoran and Turner, Suzanne Dawn and Egger, Gerda and Lagger, Sabine and Kenner, Lukas},
   article_location = {LONDON},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s12943-022-01542-8},
   keywords = {Prostate cancer; Senescence; Metastasis; KMT2C; MYC; p16(INK4A)},
   language = {eng},
   issn = {1476-4598},
   journal = {Molecular Cancer},
   title = {KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis},
   url = {https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01542-8},
   volume = {21},
   year = {2022}
}

TY  - JOUR
ID  - 2212060
AU  - 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
PY  - 2022
TI  - KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
JF  - Molecular Cancer
VL  - 21
IS  - 1
SP  - 89
EP  - 89
PB  - BioMed Central
SN  - 14764598
KW  - Prostate cancer
KW  - Senescence
KW  - Metastasis
KW  - KMT2C
KW  - MYC
KW  - p16(INK4A)
UR  - https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-022-01542-8
N2  - 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.
ER  -

LIMBERGER, Tanja, Michaela SCHLEDERER, Karolína TRACHTOVÁ, Ines Garces de los Fayos ALONSO, Jiaye YANG, Sandra HOEGLER, Christina STERNBERG, Vojtěch BYSTRÝ, Jan OPPELT, Boris TICHÝ, Margit SCHMEIDL, Petra KODAJOVA, Anton JAEGER, Heidi A NEUBAUER, Monika OBERHUBER, Belinda S SCHMALZBAUER, Šárka POSPÍŠILOVÁ, Helmut DOLZNIG, Wolfgang WADSAK, Zoran CULIG, Suzanne Dawn TURNER, Gerda EGGER, Sabine LAGGER and Lukas KENNER. KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis. \textit{Molecular Cancer}. LONDON: BioMed Central, 2022, vol.~21, No~1, p.~89-107. ISSN~1476-4598. Available from: https://dx.doi.org/10.1186/s12943-022-01542-8.

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