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KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-Seq 2]

ABSTRACT: KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-Seq 2]

PROVIDER: PRJNA517820 | ENA |

REPOSITORIES: ENA

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KMT9 writes the histone mark H4K12me1 and controls metabolism and proliferation of castration-resistant prostate cancer cells

Project description:Posttranslational modifications of histones such as methylation regulate chromatin structure and gene expression. Methylation of histone lysine residues is generally performed by SET domain methyltransferases. Here, we identify the heterodimeric C21orf127/TRMT112 complex as a specific histone methyltransferase. Assembly of the seven-b-strand protein C21orf127 (also named Hemk2, N6amt1 or PrmC) with TRMT112 is essential to form an active enzyme, hereafter named KMT9 that writes the histone mark H4K12me1 in vitro and in vivo. The H4K12me1 mark is enriched at promoters of KMT9 target genes and co-localises with the active histone mark H4K12ac. By controlling expression of genes involved in energy metabolism, KMT9 regulates oxidative phosphorylation in androgen receptor-dependent and -independent prostate tumour cells. Importantly, KMT9 depletion severely affects proliferation of castration and enzalutamide-resistant prostate cancer cells and xenograft tumours. Together, our data link the writing of the H4K12me1 histone mark by KMT9 with KMT9-dependent gene expression, which in consequence regulates energy metabolism and proliferation. KMT9 executes these functions independently of androgen receptor and androgen signalling thus, providing a promising paradigm for the treatment of castration resistant prostate cancer.

2019-03-11 | PXD008965 | Pride

KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells

Project description:This SuperSeries is composed of the SubSeries listed below. Posttranslational modifications of histones such as methylation regulate chromatin structure and gene expression. Methylation of histone lysine residues is generally performed by SET domain methyltransferases. Here, we identify the heterodimeric C21orf127/TRMT112 complex as a histone methyltransferase. Assembly of the seven-b-strand protein C21orf127 (also named Hemk2, N6amt1 or PrmC) with TRMT112 is essential to form an active enzyme, hereafter named KMT9 that writes the histone mark H4K12me1 in vitro and in vivo. We characterized the recognition mode of H4K12 by KMT9 that is formed by the assembly of KMT9a with KMT9b by solving the co-crystal structure. Genome-wide analyses revealed KMT9 and H4K12me1 enrichment at promoters of KMT9 target genes. By controlling expression of genes involved in cell cycle regulation, KMT9 regulates proliferation of androgen receptor-dependent and -independent prostate tumour cells. Importantly, KMT9 depletion severely affects proliferation of castration- and enzalutamide-resistant prostate cancer cells and xenograft tumours. Together, our data link the writing of the H4K12me1 histone mark by KMT9 with KMT9-dependent gene expression, which in consequence regulates cell cycle and proliferation. KMT9 executes these functions independently of androgen receptor and androgen signalling thus, providing a promising paradigm for the treatment of castration resistant prostate cancer.

2019-06-26 | GSE117536 | GEO

KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-seq]

Project description:KMT9 is formed by the assembly of KMT9a and KMT9b and writes the H4K12me1 mark. The objectives of this study is to identify KMT9a, KMT9b, and H4K12me1 locations by ChIP-seq in the androgen-independent PC-3M prostate cancer cells and to show that upon KMT9a knockdown the levels of H4K12me1 mark decrease.

2019-06-26 | GSE117534 | GEO

KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-seq]

Project description:KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-seq]

| PRJNA482409 | ENA

KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [RNA-seq]

Project description:The aim of the RNA-seq was to identify the KMT9 transcriptome in PC-3M cells. The MCF10A breast epithelial cells that do not express KMT9a were used to show that the siRNA against KMT9 show no off-target effects.

2019-06-26 | GSE117535 | GEO

Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

Project description:Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 an attractive therapeutic target. Here, we report the development of the first-in-class, potent and selective KMT9 inhibitor (compound 4, KMI169) through structure-based drug design. KMI169 functions as a bi-substrate inhibitor targeting the SAM and substrate binding pockets of KMT9 and exhibits high potency, selectivity, and cellular target engagement. KMT9 inhibition selectively downregulates target genes involved in transcription and cell cycle regulation and impairs proliferation of tumours cells including castration- and enzalutamide-resistant prostate cancer cells. Together, KMI169 represents a valuable tool to probe cellular KMT9 functions and paves the way for the development of clinical inhibitors as therapeutic options to treat malignancies such as therapy-resistant prostate cancer.

2023-12-31 | GSE235595 | GEO

KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells

Project description:KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells

| PRJNA482404 | ENA

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

Project description:Background: Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study we aimed to identify the function of KMT9 in lung cancer which has remained elusive so far. Methods: We linked full transcriptome and proteome analyses of A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry with functional cell culture, real-time proliferation and flow cytometry assays. Results: KMT9 is expressed in lung cancer tissue and cell lineswith high levels of KMT9 correlating with poor patient survival. We identified 460 overlapping genes and proteins that are deregulated upon knock-down of KMT9alpha in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9alpha inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells. Conclusions: The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy.

2020-05-26 | PXD014145 | Pride

KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [RNA-seq]

Project description:KMT9a writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [RNA-seq]

| PRJNA482410 | ENA

KMT9 writes the H4K12me1 histone mark and controls metabolism and proliferation of castration-resistant prostate cancer cells [ChIP-Seq 2]

Project description:The aim of the study is to identify KMT9a target genes in PC-3M cells

2019-06-26 | GSE125882 | GEO