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Deficiency of ERO1 and activation of protein translation synergistically impair breast tumor resilience

ABSTRACT: Deficiency of ERO1 and activation of protein translation synergistically impair breast tumor resilience

PROVIDER: PRJEB52741 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR9712180.fastq.gz	Fastqsanger.gz
	ERR9712190.fastq.gz	Fastqsanger.gz
	ERR9712200.fastq.gz	Fastqsanger.gz
	ERR9712181.fastq.gz	Fastqsanger.gz
	ERR9712191.fastq.gz	Fastqsanger.gz

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Deficiency of ERO1 and activation of protein translation synergistically impair breast tumor resilience

Project description:Endoplasmic reticulum (ER) stress triggers an adaptive response which fosters tumor cell survival and resilience to stress conditions. Activation of the endoplasmic reticulum stress response, through its PERK branch, promotes the phosphorylation of the α-subunit of translation initiation factor eIF2alpha, thereby repressing general protein translation and selectively augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase ERO1. Here, we show that ISRIB, a small molecule, which inhibits the action of the phosphorylated α-subunit of eIF2, thereby activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1 enfeebling tumor growth and spreading. ISRIB represses CHOP signal but surprisingly does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a prominent perturbing effect on ERO1 deficient Triple-Negative breast cells, which have adapted to live with low client protein load, while ERO1 deficiency selectively impairs VEGF-dependent angiogenesis. Strikingly, ERO1-deficient Triple Negative Breast Cancer xenografts have augmented ER stress response and PERK branch. In vivo, ISRIB synergistically with ERO1 deficiency inhibits the growth of Triple-Negative Breast cancer xenografts by impairing proliferation and angiogenesis, while it is not effective on the xenograft counterparts with ERO1. In summary, these results demonstrate that ISRIB together with ERO1 deficiency synergistically shatters a feature of the adaptive ER stress response while ERO1 deficiency selectively impairs angiogenesis in tumors, thereby together promoting tumor cytotoxicity. Therefore, our findings suggest two surprising findings in breast tumors: ERO1 is not regulated via CHOP and ISRIB represents a therapeutic option to efficiently inhibit tumor progression in those tumors with limited ERO1 and high PERK.

2022-07-20 | E-MTAB-11313 | biostudies-arrayexpress

Endoplasmic reticulum oxidoreductin 1-alpha deficiency and activation of protein translation synergistically impair breast tumour resilience.

Project description:Background and purposeEndoplasmic reticulum (ER) stress triggers an adaptive response in tumours which fosters cell survival and resilience to stress. Activation of the ER stress response, through its PERK branch, promotes phosphorylation of the α-subunit of the translation initiation factor eIF2, thereby repressing general protein translation and augmenting the translation of ATF4 with the downstream CHOP transcription factor and the protein disulfide oxidase, ERO1-alpha EXPERIMENTAL APPROACH: Here, we show that ISRIB, a small molecule that inhibits the action of phosphorylated eIF2alpha, activating protein translation, synergistically interacts with the genetic deficiency of protein disulfide oxidase ERO1-alpha, enfeebling breast tumour growth and spread.Key resultsISRIB represses the CHOP signal, but does not inhibit ERO1. Mechanistically, ISRIB increases the ER protein load with a marked perturbing effect on ERO1-deficient triple-negative breast cancer cells, which display impaired proteostasis and have adapted to a low client protein load in hypoxia, and ERO1 deficiency impairs VEGF-dependent angiogenesis. ERO1-deficient triple-negative breast cancer xenografts have an augmented ER stress response and its PERK branch. ISRIB acts synergistically with ERO1 deficiency, inhibiting the growth of triple-negative breast cancer xenografts by impairing proliferation and angiogenesis.Conclusion and implicationsThese results demonstrate that ISRIB together with ERO1 deficiency synergistically shatter the PERK-dependent adaptive ER stress response, by restarting protein synthesis in the setting of impaired proteostasis, finally promoting tumour cytotoxicity. Our findings suggest two surprising features in breast tumours: ERO1 is not regulated via CHOP under hypoxic conditions, and ISRIB offers a therapeutic option to efficiently inhibit tumour progression in conditions of impaired proteostasis.

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Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence

Project description:Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence

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Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

Project description:Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes

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Decoding of translation-regulating entities reveals heterogeneous translation deficiency patterns in cellular senescence

Project description:Cellular senescence constitutes a generally irreversible proliferation barrier, accompanied by macromolecular damage and metabolic rewiring. Several senescence types have been identified based on the initiating stimulus, such as replicative (RS), stress-induced (SIS) and oncogene-induced senescence (OIS). Reduced protein synthesis is considered a senescence hallmark, but whether this trait pertains to various senescence subtypes and if distinct molecular mechanisms are involved remain largely unknown. Here, we analyze large published or experimentally produced RNA-seq and Ribo-seq datasets to determine whether major translation-regulating entities such as ribosome stalling, the presence of uORFs/dORFs and IRES elements may differentially contribute to translation deficiency in senescence subsets. We show that translation-regulating mechanisms may not be directly relevant to RS, however uORFs are significantly enriched in SIS. Interestingly, ribosome stalling, uORF/dORF patterns and IRES elements comprise predominant mechanisms upon OIS, strongly correlating with Notch pathway activation. Our study provides for the first time evidence that major translation dysregulation mechanisms/patterns occur during cellular senescence, but at different rates depending on the stimulus type. The degree at which those mechanisms accumulate directly correlates with translation deficiency levels. Our thorough analysis contributes to elucidating crucial and so far unknown differences in the translation machinery and ribosome biogenesis between senescence subsets.

2023-08-31 | GSE225095 | GEO

METTL5 deficiency induces lung cancer regression via mitochondrial translation reduction

Project description:Cellular protein synthesis occurs through two types of translation: cytoplasmic and mitochondrial. These two types of translation operate independently but in coordination to regulate cell survival and death. Methyltransferase-like 5 (METTL5) has been found to play a role in directing the m6A modification of rRNA, which in turn controls cytoplasmic translation and impacts the decisions related to cell fate. In this study, we employed Ribo-seq to explore the effects of METTL5 deficiency on both cytoplasmic and mitochondrial translation.

2025-03-01 | GSE272389 | GEO

Neurons shift translational control to secure proteostatic resilience during ER stress

Project description:Proteostasis is essential for survival and particularly important for highly specialized post mitotic cells like neurons. Transient reduction of protein synthesis by protein kinase R–like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. We employed PERK-deficient neuron and astrocyte monocultures to investigate the mechanisms underlying neuron-specific ER stress resilience in the absence of PERK.

2022-06-13 | GSE200742 | GEO

Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [ChIP-seq]

Project description:Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [ChIP-seq]

| PRJNA544087 | ENA

Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [Hi-C]

Project description:Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [Hi-C]

| PRJNA544086 | ENA

Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [RNA-seq]

Project description:Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes [RNA-seq]

| PRJNA544088 | ENA