ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability
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ABSTRACT:
PROVIDER: PRJNA242259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1197241.fastq.gz | Fastqsanger.gz | |||
| SRR1197241_1.fastq.gz | Fastqsanger.gz | |||
| SRR1197241_2.fastq.gz | Fastqsanger.gz | |||
| SRR1197961.fastq.gz | Fastqsanger.gz | |||
| SRR1197961_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress. Immortalized human mammary epithelial cells were infected with retrovirus expressing H-RASV12 with or without a retrovirus expressing ZEB1.
2015-12-31 | E-GEOD-55989 | biostudies-arrayexpress
Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress.
2015-12-31 | GSE55989 | GEO
Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour-initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high-grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress.
2015-12-31 | GSE55688 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-12-31 | E-GEOD-56031 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-12-31 | GSE56031 | GEO
Project description:ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability [Affymetrix]
| PRJNA240556 | ENA
Project description:ZEB1 expression prevents DNA replication stress in cancer stem cells and delays chromosomal instability [Agilent]
| PRJNA279696 | ENA
Project description:DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of H3-H4 supply chains
| PRJNA1065442 | ENA
Project description:Chromosomal instability (CIN) is a hallmark of cancer, and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous inflammatory response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose envelopes frequently rupture exposing their DNA content to the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-kB signaling. Genetic suppression of CIN significantly delays metastasis in transplantable tumor models, whereas inducing chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. In contrast to primary tumors, human and mouse metastases strongly select for CIN, in part, due to its ability to enrich for metastasis-initiating mesenchymal subpopulations, offering an opportunity to target chromosome segregation errors for therapeutic benefit.
2018-01-15 | GSE98183 | GEO
Project description:The centromeric histone H3 variant CENP-A is overexpressed in many cancers. The mislocalization of CENP-A to noncentromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. However, pathways that promote or prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen for regulators of CENP-A localization which identified DNAJC9, a J-domain protein implicated in histone H3–H4 protein folding, as a factor restricting CENP-A mislocalization. Cells lacking DNAJC9 exhibit mislocalization of CENP-A throughout the genome, and CIN phenotypes. Global interactome analysis showed that DNAJC9 depletion promotes the interaction of CENP-A with the DNA-replication-associated histone chaperone MCM2. CENP-A mislocalization upon DNAJC9 depletion was dependent on MCM2, defining MCM2 as a driver of CENP-A deposition at ectopic sites when H3–H4 supply chains are disrupted. Cells depleted for histone H3.3, also exhibit CENP-A mislocalization. In summary, we have defined novel factors that prevent mislocalization of CENP-A, and demonstrated that the integrity of H3–H4 supply chains regulated by histone chaperones such as DNAJC9 restrict CENP-A mislocalization and CIN.
2024-04-11 | PXD043961 | Pride