KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
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PROVIDER: PRJNA773757 | ENA |
REPOSITORIES: ENA
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Project description:Frequent truncating 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. To investigate the functional impact of these mutations we deleted the C-terminal catalytic core motif of KMT2C specifically in the prostate epithelium of mice. We show here that impaired KMT2C methyltransferase activity drives proliferation and, when combined with loss of the tumour suppressor PTEN, triggers metastatic dissemination and reduces life expectancy. In our model system and human prostate cancer samples we show that KMT2C-mutated tumours activate the proliferative MYC signalling axis and fail to express the oncogene-induced cell cycle repressor p16INK4A. In addition, we observe a striking reduction in disease-free survival of patients with KMT2C-mutated prostate cancer. Thus, we identify truncated KMT2C as a driver of aggressive prostate cancer.
2022-05-02 | GSE186413 | GEO
Project description:BackgroundFrequent 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.MethodsTo 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.ResultsWe 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.ConclusionsWe 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.
| S-EPMC8966196 | biostudies-literature
Project description:Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus
| PRJNA336025 | ENA
Project description:Mutations in genes encoding epigenetic regulators are among the most frequent somatic events in human cancers. For example, missense and truncating mutations in the MLL3 (KTM2C) histone H3K4-methyltransferase gene can be found in several tumor types. MLL3 is a member of the mixed lineage leukemia gene family and component of the mammalian COMPASS/like complex that promotes gene expression by establishing chromatin modifications favoring gene activation. While Mll3 loss of function promotes tumorigenesis in mice, the molecular targets and biological processes underlying its anti-neoplastic effects remain unknown. Here we combine powerful genetic, genomic, and animal modeling approaches to demonstrate that Mll3 suppresses hepatocellular carcinoma (HCC) by promoting activation of the Cdkn2a (Ink4a/Arf) locus. Hence, disruption of Mll3 using CRISPR/Cas9-mediated genome editing or by RNA interference using short hairpin RNAs cooperates with the Myc oncogene to drive tumorigenesis, producing tumors with reduced H3K4 methylation at multiple gene regulatory elements and low levels of p16Ink4a and p19Arf expression. These results place MLL3 in an established tumor suppressor network and reveal how disruption of a conserved mechanism of epigenetic regulation can alter CDKN2A action and cancer development.
2017-08-01 | GSE85053 | GEO
Project description:Mutations in genes encoding epigenetic regulators are among the most frequent somatic events in human cancers. For example, missense and truncating mutations in the MLL3 (KTM2C) histone H3K4-methyltransferase gene can be found in several tumor types. MLL3 is a member of the mixed lineage leukemia gene family and component of the mammalian COMPASS/like complex that promotes gene expression by establishing chromatin modifications favoring gene activation. While Mll3 loss of function promotes tumorigenesis in mice, the molecular targets and biological processes underlying its anti-neoplastic effects remain unknown. Here we combine powerful genetic, genomic, and animal modeling approaches to demonstrate that Mll3 suppresses hepatocellular carcinoma (HCC) by promoting activation of the Cdkn2a (Ink4a/Arf) locus. Hence, disruption of Mll3 using CRISPR/Cas9-mediated genome editing or by RNA interference using short hairpin RNAs cooperates with the Myc oncogene to drive tumorigenesis, producing tumors with reduced H3K4 methylation at multiple gene regulatory elements and low levels of p16Ink4a and p19Arf expression. These results place MLL3 in an established tumor suppressor network and reveal how disruption of a conserved mechanism of epigenetic regulation can alter CDKN2A action and cancer development.
2017-08-01 | GSE85049 | GEO
Project description:Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multi-omics analyses. We found that loss of KMT2C, an H3K4 methyltransferase frequently mutated in extensive stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C deficient SCLC through repressing metastasis promoting MEIS/HOX genes. Further, S-(5’-Adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a new epigenetic therapeutic vulnerability.
2022-02-23 | GSE161570 | GEO
Project description:This study demonstrate the biological function of JAG1 intracellular domain (JICD1). In order to elucidate the characteristics of JICD1, HA-JICD1 and NICD1 overexpressed in murine Ink4a-/- astrocytes.
2021-02-01 | GSE126853 | GEO
Project description:KMT2C and KMT2D are two of the most frequently mutated genes in bladder cancer and in histologically normal urothelium. In this study, we developed mouse models to investigate the molecular mechanism of Kmt2c/d loss in urothelial tumorigenesis.
2024-08-09 | GSE264514 | GEO
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2009-02-25 | E-NCMF-22 | biostudies-arrayexpress
Project description:The histone 3 lysine 4 (H3K4) monomethylase KMT2C is mutated across several cancer types, however the effects of mutations on epigenome organization, gene expression and cell growth are not clear. To study effects of KMT2C expression in CRC cells we restored one allele to wild type KMT2C in the two CRC cell lines RKO and HCT116, which both are homozygous KMT2C c.8390delA mutant, by gene editing. RNA sequencing was performed to profile gene expression when KMT2C was restored in RKO and HCT116 cells.
2020-06-01 | GSE131507 | GEO