Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE186413 | GEO | 2022/05/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

Project description:KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis

| PRJNA773757 | ENA

Deciphering epigenetic and transcriptional alterations after Kmt2c/2d knock-out in mouse bladder urothelial cells

Project description:KMT2C and KMT2D are two of the most frequently mutated genes in histologically normal human bladder urothelium. In this study, we sought to model Kmt2c/d LOF mutations and investigate the biological mechanism of Kmt2c/d LOF mutations in bladder cancer development.

2024-08-09 | GSE180947 | GEO

Gene regulation by restoration of KMT2C in human colorectal cancer cells HCT116 and RKO

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

KMT2C Loss Promotes Small Cell Lung Cancer Metastasis through DNMT3A-mediated Epigenetic Reprogramming

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

Restoration of KMT2C in human colorectal cancer cell lines HCT116 and RKO reinforces genome wide H3K4me1 profiles

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. Chromatin was analysed by ChIP-sequencing using the Diagenode iDeal ChIP-seq kit for Histones and the H3K4me1 specific antibody (Abcam ab8895).

2020-06-01 | GSE131755 | GEO

Epigenetic and transcriptional alterations with Kmt2c and Kmt2d knockout

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

Epigenetic and transcriptional alterations with Kmt2c and Kmt2d loss in urothelial cells

2024-08-09 | GSE236370 | GEO

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 [scRNA-seq]

Project description:Histone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.

2024-04-24 | GSE237289 | GEO

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 [ChIP-seq]

2024-04-24 | GSE237390 | GEO

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3 [RNA-seq]

2024-04-24 | GSE237287 | GEO