KMT2C methyltransferase domain regulated INK4A expression suppresses prostate cancer metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA773757 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16538556.fastq.gz | Fastqsanger.gz | |||
| SRR16538557.fastq.gz | Fastqsanger.gz | |||
| SRR16538558.fastq.gz | Fastqsanger.gz | |||
| SRR16538559.fastq.gz | Fastqsanger.gz | |||
| SRR16538560.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Mll3 suppresses tumorigenesis by activating the Ink4a/Arf locus
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Project description:Cancer cells can spread from their original sites to both other organs and other sites within the same organs. One example of the latter is the intrapulmonary metastasis (IPM) of lung cancer, which is associated with poor prognosis but barely studied. In this study, we compared the genomic profiles of lung cancers with and without IPM and identified a hotspot mutation in KMT2C p.C391*, as an IPM-specific "driver" mutation. Using recently developed mouse models with single primary lung tumors, we demonstrated that KMT2C p.C391*, but not the loss of wild-type Kmt2c, promotes IPM in mice. Patients with IPM and mice with tumors harboring KMT2C p.C391* exhibited reduced alveolar macrophages and natural killer cells. Depleting these innate immune cell populations, mimicking the effects of KMT2C p.C391*, enhanced the survival and growth of tumor cells within the alveolar space. Mechanistically, KMT2C p.C391*, which lacks the C-terminal SET domain essential for H3K4 methyltransferase activity and gene activation, paradoxically represses gene expression. This repressive function appears to be mediated by SETDB1 and its downstream H3K9me3. And KMT2C p.C391* globally suppresses the expression of transposable elements (TEs), potentially facilitating immune evasion of tumor cells within the alveolar environment by reducing the interferon pathways. Our findings identify KMT2C p.C391* as a novel IPM-specific mutation with diagnostic potential and highlight the roles of TEs and innate immunity in IPM, offering promising avenues for clinical intervention.
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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.
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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.
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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:Prostate cancer (PCa) is a leading cause of male morbidity and mortality. Epigenetic modifier abnormalities are becoming a driving event in prostate cancer (PCa). The specific role of KMT2C, a histone methyltransferase that is frequently aberrant in various tumors, is poorly understood in PCa. This study aimed to reveal the potential carcinogenic role of KMT2C in PCa. Herein we confirmed the KMT2C overexpression in PCa, at transcript and protein level. Knockdown KMT2C in VCaP and LNCaP cells attenuated malignant phenotype, suppressing cell viability, clony, and migration. Consistently, stable KMT2C depletion effectively decreases tumor growth by about 70% in vivo. Mechanically, the results suggest that CLDN8 and ITGAV are two key downstream genes of KMT2C.
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Project description:Rattus norvegicus Kmt2c, lysine methyltransferase 2C [Source:RGD Symbol;Acc:1587205], is differentially expressed in 21 experiment(s);
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Project description:Rattus norvegicus Kmt2c, lysine methyltransferase 2C [Source:RGD Symbol;Acc:1587205], is expressed in 5 baseline experiment(s);
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