KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Abstract

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 p16INK4A. 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.

Comprehensive germline and somatic genomic profiles of Chinese patients with biliary tract cancer

“…Although NCOR1 and KMT2C/D alterations were relatively common in this study ( Supplementary Figure 1 ), there were few studies investigating on their oncogenic role in BTC. Previous studies have found that NCOR1 and KMT2C/D play oncogenic roles in bladder cancer ( 24 ), colorectal cancer ( 25 ), prostate cancer ( 26 , 27 ), and lymphomagenesis ( 28 ). In addition, other important BTC genes, including PBRM1 (10%), BRAF (8%), BAP1 (6%), PTEN (5%), IDH1 (5%), IDH2 (5%), and NRAS (2%), were also identified with a relatively low prevalence in our cohort ( Figure 1A ).…”

A pan-cancer interrogation of intronic polyadenylation and its association with cancer characteristics

“…KMT2C mutations contribute to tumorigenesis and are associated with poor survival rates (61,62). In particular, the complete loss of KMT2C due to truncating mutations is correlated with significantly shorter progression-free survival in patients with breast cancer patients who undergo estrogen therapy (63) and in patients with metastatic prostate cancer (64). The IPA-associated loss of KMT2C may have the functions that need further validation.…”

A pan-cancer interrogation of intronic polyadenylation and its association with cancer characteristics

“…KMT2C mutations contribute to tumorigenesis and are associated with poor survival rates 55,56 . In particular, the complete loss of KMT2C due to truncating mutations is correlated with significantly shorter progression-free survival in patients with breast cancer patients who undergo estrogen therapy 57 and in patients with metastatic prostate cancer 58 . The IPAassociated loss of KMT2C may have the functions that need further validation.…”