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

ABSTRACT: The aim of the study is to identify KMT9a target genes in A549 cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE131016 | GEO | 2021/12/31

REPOSITORIES: GEO

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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

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

Project description:BackgroundLung 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 that acts 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.MethodsWe unraveled the KMT9 transcriptome and proteome in A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry and linked them with functional cell culture, real-time proliferation and flow cytometry assays.ResultsWe show that KMT9α and -β subunits of KMT9 are expressed in lung cancer tissue and cell lines. Importantly, high levels of KMT9α correlate with poor patient survival. We identified 460 genes that are deregulated at the RNA and protein level upon knock-down of KMT9α 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 KMT9α inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells.ConclusionsThe 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.

| S-EPMC7027090 | biostudies-literature

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

Project description:Depletion of histone methyl transferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

| PRJNA542325 | ENA

KMT9 controls growth and stemness of colorectal cancer [ChIP-seq]

Project description:The aim of the study is to identify KMT9a target genes in AOMDSS tumour organoids

2021-11-29 | GSE150502 | 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 controls growth and stemness of colorectal cancer [single-cell RNA-seq]

Project description:The aim of the study is to identify cell-specific KMT9a target genes in AOMDSS tumour organoids

2021-11-29 | GSE150505 | GEO

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

Rotenone inhibits autophagic flux prior to inducing cell death.

Project description:Rotenone, which selectively inhibits mitochondrial complex I, induces oxidative stress, α-synuclein accumulation, and dopaminergic neuron death, principal pathological features of Parkinson's disease. The autophagy-lysosome pathway degrades damaged proteins and organelles for the intracellular maintenance of nutrient and energy balance. While it is known that rotenone causes autophagic vacuole accumulation, the mechanism by which this effect occurs has not been thoroughly investigated. Treatment of differentiated SH-SY5Y cells with rotenone (10 μM) induced the accumulation of autophagic vacuoles at 6 h and 24 h as indicated by Western blot analysis for microtubule associated protein-light chain 3-II (MAP-LC3-II). Assessment of autophagic flux at these time points indicated that autophagic vacuole accumulation resulted from a decrease in their effective lysosomal degradation, which was substantiated by increased levels of autophagy substrates p62 and α-synuclein. Inhibition of lysosomal degradation may be explained by the observed decrease in cellular ATP levels, which in turn may have caused the observed concomitant increase in acidic vesicle pH. The early (6 h) effects of rotenone on cellular energetics and autophagy-lysosome pathway function preceded the induction of cell death and apoptosis. These findings indicate that the classical mitochondrial toxin rotenone has a pronounced effect on macroautophagy completion that may contribute to its neurotoxic potential.

| S-EPMC3526971 | biostudies-other

Pentamidine inhibits prostate cancer progression via selectively inducing mitochondrial DNA depletion and dysfunction.

Project description:ObjectivesWe investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment.Materials and methodsProstate cancer cell lines and epithelial RWPE-1 cells were used in the study. Cell viability, wound-healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA-seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti-tumour effects of pentamidine in vivo.ResultsPentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells.ConclusionsPentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria-targeted therapeutic agent for prostate cancer.

| S-EPMC6985668 | biostudies-literature

The anti-apoptotic Bcl-B protein inhibits BECN1-dependent autophagic cell death.

Project description:Bcl-2 family members are key modulators of apoptosis that have recently been shown to also regulate autophagy. It has been previously reported that Bcl-2 and Bcl-X(L) bind and inhibit BECN1, an essential mediator of autophagy. Bcl-B is an anti-apoptotic member of the Bcl-2 family that possesses the four BH (Bcl-2 homology) domains (BH1, BH2, BH3 and BH4) and a predicted C-terminal trans-membrane domain. Although the anti-apoptotic properties of Bcl-B are well characterized, its physiological function remains to be established. In the present study, we first established that Bcl-B interacts with the BH3 domain of BECN1. We also showed that Bcl-B overexpression reduces autophagy triggered by a variety of pro-autophagic stimuli. This impairment of autophagy was closely related to the capacity of Bcl-B to bind to BECN1. Importantly, we have demonstrated that Bcl-B knockdown triggers autophagic cell death and sensitizes cells to amino acid starvation. The cell death induced by Bcl-B knockdown was partially dependent on components of the autophagy machinery (LC3; BECN1; ATG5). These findings reveal a new role of Bcl-B in the regulation of autophagy.

| S-EPMC3405843 | biostudies-other

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