Depletion of histone methyl transferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death
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PROVIDER: PRJNA542325 | ENA |
REPOSITORIES: ENA
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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
Project description:The aim of the study is to identify KMT9a target genes in A549 cells
2021-12-31 | GSE131016 | GEO
Project description: Not available
| S-EPMC7027090 | biostudies-literature
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
Project description:Novel treatment modalities are imperative for the challenging management of muscle-invasive and metastatic BC to improve patient survival rates. The recently identified lysine methyltransferase (KMT) 9, an obligate heterodimer composed of KMT9α and KMT9β, regulates the growth of various types of tumors such as prostate, lung and colon cancer. While overexpression of KMT9α was previously observed to be associated with aggressive basal-like MIBC in an analysis of patients’ tissue samples, a potential functional role of KMT9 in this type of cancer has not been investigated to date. In this study, we show that KMT9 regulates proliferation and migration of various MIBC cell lines with different genetic mutations. KMT9α depletion results in differential expression of genes involved in the regulation of the cell cycle, cell adhesion and migration. Reduced cell proliferation upon KMT9α depletion is also observed in Pten/Trp53 knockout bladder tumor organoids, which cannot be rescued with an enzymatically inactive KMT9α mutant. In accordance with the idea that the catalytic activity of KMT9 is required for the control of cellular processes in MIBC, a recently developed small molecule inhibitor of KMT9 (KMI169) also impairs cancer cell proliferation. Since KMT9α depletion also restricts the growth of xenografts in mice, our data suggest that KMT9 is an actionable novel therapeutic target for the treatment of MIBC.
2024-05-01 | GSE255344 | GEO
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
Project description:Cells can survive effector caspase (caspase 3/7) activation in response to transient apoptotic stimuli, a process named anastasis. To characterize the molecular events that occur during anastasis, we performed whole transcriptome RNA sequencing of untreated, apoptotic, and recovering cells. We found that anastasis is an active, two-stage program with unique transcriptional profiles in each stage. We also identified 10 genes that specific to the early stage of anastasis.
2017-07-31 | GSE86480 | GEO
Project description:BMI1 is a polycomb protein and its overexpression has been correlated with cancer development and aggressiveness. We previously reported that v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog (MYCN)-induced BMI1 positively regulated neuroblastoma (NB) cell proliferation via the transcriptional suppression of tumor suppressors in NB cells. In order to evaluate the potential of BMI1 as a new target for NB therapy, we herein examined the effects of BMI1 reductions on NB cell differentiation and apoptotic NB cell death. BMI1 knockdown (KD) up to 7 days in NB cells significantly induced their differentiation. BMI1 depletion up to 14 days significantly induced apoptotic NB cell death along with the activation of p53, increases in p73, and induction of p53 family downstream molecules. BMI1 depletion in vivo markedly suppressed NB xenograft tumor growth. A pathological analysis using the TUNEL assay indicated the induction of apoptotic cell death. BMI1 reductions activated ATM and increased γ-H2AX in NB cells. Importantly, these DNA damage signals and apoptotic cell death were not canceled by transduction of polycomb group molecules EZH2 and RING1B. Further, EZH2 or RING1B knockdown could not induce apoptotic NB cell death at the same level of BMI1 KD. Together, BMI1 appears to be a promising target of molecular therapy for NB tumors and our report clarified, for the first time, the shared role of PcG proteins in DNA damage response of NB cells.
2022-11-08 | GSE189449 | GEO
Project description:Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer (BC) cells. To delineate COMT role in metastasis of estrogen receptor (ER) dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A BC model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). We performed comparative gene expression analysis using data obtained from RNA-seq of COMT-overexpressing and control cells in biological duplicates.
2023-02-01 | GSE203435 | GEO
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