Repression of stress-induced LINE-1 expression protects cancer cell populations from lethal drug-exposures
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74180 | GEO | 2017/07/03
SECONDARY ACCESSION(S): PRJNA301676
REPOSITORIES: GEO
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Project description:DTP heterochromatin in genomic repeat regions protects the population from drug-induced death.
2017-07-03 | GSE100751 | GEO
Project description:DTP heterochromatin in genomic repeat regions protects the population from drug-induced death.
2017-07-03 | GSE100750 | GEO
Project description:Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.
2017-07-03 | GSE73874 | GEO
Project description:Merkel cell carcinoma is a skin cancer associated with the Merkel cell polyomavirus (MCPyV) which is found integrated in the genome of the tumor cells. Here 4 MCPyV-positive tumor cell lines (AlDo, LoKe, BroLi and WoWe) were analyzed by comparative gernomic hybridization to define further genetic alterations. Corresponding peripheral blood lymphocytes (PBL) in case of AlDo and LoKe, purified T cells in case of BroLi and Tumor-derived but virus-negative cells of unknown origin (WoWe1) in case of WoWe served as controls.
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Project description:Repression of stress-induced LINE-1 expression protects cancer cell populations from lethal drug-exposures
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Project description:BACKGROUND AND PURPOSE: Tanshinone IIA is an active component of a traditional Chinese medicine based on Salvia miltiorrhiza, which reduces sudden cardiac death by suppressing ischaemic arrhythmias. However, the mechanisms underlying the anti-arrhythmic effects remain unclear. EXPERIMENTAL APPROACH: A model of myocardial infarction (MI) in rats by ligating the left anterior descending coronary artery was used. Tanshinone IIA or quinidine was given daily, before (7 days) and after (3 months) MI; cardiac electrical activity was monitored by ECG recording. Whole-cell patch-clamp techniques were used to measure the inward rectifying K(+) current (I(K1)) in rat isolated ventricular myocytes. Kir2.1 and serum response factor (SRF) levels were analysed by Western blot and microRNA-1 (miR-1) level was determined by real-time RT-PCR. KEY RESULTS: Tanshinone IIA decreased the incidence of arrhythmias induced by acute cardiac ischaemia and mortality in rats 3 months after MI. Tanshinone IIA restored the diminished I(K1) current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited I(K1)/Kir2.1. MiR-1 was up-regulated in MI, possibly due to the concomitant increase in SRF, a transcriptional activator of the miR-1 gene, accounting for decreased Kir2.1. Treatment with tanshinone IIA prevented increased SRF and hence increased miR-1 post-MI, whereas quinidine did not. CONCLUSIONS AND IMPLICATIONS: Down-regulation of miR-1 and consequent recovery of Kir2.1 may account partially for the efficacy of tanshinone IIA in suppressing ischaemic arrhythmias and cardiac mortality. These finding support the proposal that miR-1 could be a potential therapeutic target for the prevention of ischaemic arrhythmias.
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Project description:Establishing and maintaining phenotypic heterogeneity within cell and organismal populations is an evolutionarily conserved strategy that ensures survival of the population following stressful exposures. We previously identified a transient, reversible, drug-tolerant cancer cell subpopulation that survives otherwise lethal drug exposures. Here we show that these drug-tolerant persisters (DTPs) assume a highly heterochromatic state, which requires factors that modify or bind trimethylated H3 lysine 9 (H3K9me3). The increased H3K9me3 in DTPs is largely restricted to evolutionarily young Long Interspersed Repeat elements (LINEs). This transcriptionally repressive state, which decreases the expression of these retrotransposable elements, is critical for DTP survival, and disruption of this heterochromatic state results in re-expression of LINE elements and ablation of this subpopulation. Together, these findings establish a role for epigenetic silencing of transposable elements as a population survival strategy to maintain genomic integrity in subpopulations of cancer cells during lethal drug exposures.
2017-07-03 | GSE74179 | GEO
Project description:Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even, rarely, mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Covering only first-line antituberculosis drugs, this review addresses whether and how oxidative stress and, more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection, and preexisting liver disease. Importantly, these comorbid conditions are associated with oxidative stress. Thus, the shared pathogenetic mechanism(s) for liver injury might be in operation due to disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. More translational research to unravel the pathogenesis, inclusive of the underlying molecular basis, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is clinical research pertaining to the advances in therapy with antioxidants and drugs related to antioxidants, especially those for management of mitochondrial dysfunction. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.
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Project description:Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate "semi-conservatively," e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of "lethal isolation." Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently large populations.
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Project description:This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.
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