MAGI1 prevents senescence and promotes the DNA damage response in ER+ breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA997339 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25388304.fastq.gz | Fastqsanger.gz | |||
| SRR25388305.fastq.gz | Fastqsanger.gz | |||
| SRR25388306.fastq.gz | Fastqsanger.gz | |||
| SRR25388307.fastq.gz | Fastqsanger.gz | |||
| SRR25388308.fastq.gz | Fastqsanger.gz |
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Project description:MAGI1 acts as tumor suppressor in estrogen receptor positive (ER+) breast cancer (BC) and its loss correlates with a more aggressive phenotype. To identify pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ MCF7 BC cell line and performed RNA-sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, cell cycle and DNA damage response affected by MAGI1 loss. Upon exposure to TNF-alpha/IFN-gamma, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence than MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition with olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored expression of DNA repair proteins and sensitized cells to fulvestrant. Analysis of human BC patients’ transcriptomic data revealed that patients with low MAGI1 levels have a higher tumor mutational burden and homologous recombination deficiency. Also, MAGI1 expression levels correlate negatively with PI3K/AKT and MAPK signaling, confirming our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER+ BC patients with low MAGI1 levels.
2023-07-26 | GSE237984 | GEO
Project description:MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer (BC), and its loss correlates with a more aggressive phenotype. To identify the pathways and events affected by MAGI1 loss, we deleted the MAGI1 gene in the ER+ MCF7 BC cell line and performed RNA sequencing and functional experiments in vitro. Transcriptome analyses revealed gene sets and biological processes related to estrogen signaling, the cell cycle, and DNA damage responses affected by MAGI1 loss. Upon exposure to TNF-α/IFN-γ, MCF7 MAGI1 KO cells entered a deeper level of quiescence/senescence compared with MCF7 control cells and activated the AKT and MAPK signaling pathways. MCF7 MAGI1 KO cells exposed to ionizing radiations or cisplatin had reduced expression of DNA repair proteins and showed increased sensitivity towards PARP1 inhibition using olaparib. Treatment with PI3K and AKT inhibitors (alpelisib and MK-2206) restored the expression of DNA repair proteins and sensitized cells to fulvestrant. An analysis of human BC patients' transcriptomic data revealed that patients with low MAGI1 levels had a higher tumor mutational burden and homologous recombination deficiency. Moreover, MAGI1 expression levels negatively correlated with PI3K/AKT and MAPK signaling, which confirmed our in vitro observations. Pharmacological and genomic evidence indicate HDACs as regulators of MAGI1 expression. Our findings provide a new view on MAGI1 function in cancer and identify potential treatment options to improve the management of ER+ BC patients with low MAGI1 levels.
| S-EPMC10417439 | biostudies-literature
Project description:Plasma membrane damage-dependent senescence is a novel senescence subtype. Here, we compare the time-resolved proteomic profiles of plasma membrane damage-dependent senescence, DNA damage-dependent senescence, and replicative senescence to find the major differences between the senescence subtypes.
2024-12-20 | PXD047976 | JPOST Repository
Project description:Inhibiting or depleting AHCY prevents senescence induction
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Project description:IMR90 ER:RAS cells were infected with 2 different lentiviral pGIPZ shRNAs against AHCY or with an empty vector (EV). We treated IMR90 ER:RAS cells with 4OHT to induce RAS activation or with vehicle (DMSO) as a non-senescent control. RNA was collected 6 days after the start of the experiment once the senescence program has been fully implemented. Our previous experiments showed that knockdown of AHCY prevents senescence. By performing RNAseq, we have unveiled that AHCY knockdown prevents upregulation of a set of genes essential for the onset of senescence and its associated secretory phenotype.
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Project description:Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide siRNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is a substrate of the DDR kinase ATM and contributes to an increase in the number of mitochondrial cristae upon DNA damage. Stable isotope labeling metabolomics indicated that this increase in cristae enhances the oxidation of fatty acids to acetyl-CoA. Notably, pharmacological activation of fatty acid oxidation alone induced senescence both in vitro and in vivo. Our findings suggest that mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
2024-10-30 | GSE272659 | GEO
Project description:Oxidative stress (OS), inflammation, and endoplasmic reticulum (ER) stress sequentially occur in the rat model of hyperoxia (HOX) induced bronchopulmonary dysplasia (BPD), and they all increase DNA damage. Tumor suppressors increase after DNA damage, followed by apoptosis or cellular senescence when the damage becomes irreparable. Although cellular senescence contributes to wound healing, its persistence will inhibit growth potential. Therefore, we hypothesized that the persistence of cellular senescence plays a role in BPD progression. We detected evidence of increased cellular senescence in rat and human BPD lungs. Foxo4-p53 binding was increased in BPD rat lungs, and inhibition of this binding attenuated BPD severity, indicating that such binding contributes to BPD's cellular senescence. Treatment with tauroursodeoxycholic acid (TUDCA) decreases ER stress. N-Acetyl-lysyltyrosylcysteine-amide (KYC) reduced toxic oxidant production by myeloperoxidase (MPO) and subsequent OS and inflammation. Both agents effectively decreased cellular senescence. Concomitantly, alveolar complexity and the number of type 2 alveolar cells increased, indicating that MPO-mediated OS and ER stress preceded cellular senescence in BPD rat pup lungs. These data suggest that cellular senescence plays an essential role in BPD progression. Reducing MPO toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression. Using multiomic data to investigate the role of cellular senescence in the development of BPD in rat model.
2024-01-01 | GSE223745 | GEO
Project description:Cellular senescence is a stress-induced permanent cell cycle arrest typically accompanied by expression of the cyclin-dependent kinase inhibitor p16. Recent studies have suggested that p16-expressing senescent cells accumulate in the body with age and play a causative role in aging. Various stresses, such as telomere shortening and oncogene activation, induce cellular senescence by generating DNA damage. However, how DNA damage leads to p16 expression is incompletely understood. We identified BNIP3 in a genome-wide siRNA screen for genes involved in p16 expression upon DNA damage. Mass spectrometric analysis of BNIP3-binding proteins yielded the DDR kinase ATM and components of the mitochondrial contact site and cristae organizing system (MICOS) complex. We found that BNIP3 increases the number of mitochondrial cristae upon DNA damage by electron microscopy. Metabolomic analysis linked BNIP3 to altered acetyl-CoA metabolism during DNA damage-induced senescence. We found that BNIP3 facilitates the oxidation of fatty acids to acetyl-CoA, an acetyl group donor, and promotes histone acetylation around the p16 gene and associated p16 expression. Our findings suggest that DDR signaling to mitochondria via BNIP3 promotes p16 expression through fatty acid oxidation and histone acetylation.
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2010-10-07 | E-GEOD-24500 | biostudies-arrayexpress