Transcriptional coregulator NUPR1 maintains tamoxifen resistance in breast cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA408094 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6053903_1.fastq.gz | Fastqsanger.gz | |||
| SRR6053903_2.fastq.gz | Fastqsanger.gz | |||
| SRR6053904_1.fastq.gz | Fastqsanger.gz | |||
| SRR6053904_2.fastq.gz | Fastqsanger.gz | |||
| SRR6053905_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
Similar Datasets
Project description:To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
2018-04-27 | GSE104050 | GEO
Project description:To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
| S-EPMC7862277 | biostudies-literature
Project description:In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence in vitro and tumor suppression in vivo. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers.
2016-06-05 | GSE68873 | GEO
Project description:The majority of prostate cancer (PCa) patients treated with docetaxel develop resistance to it. In order to better understand the mechanism behind the acquisition of resistance, we conducted single cell total RNA sequencing (sctotal RNA-seq) of docetaxel sensitive and resistant variants of DU145 and PC3 PCa cell lines. Overall, sensitive and resistant cells clustered separately. However, for both cell lines we identified rare sensitive cells that clustered with the resistant cells indicating resistant cells pre-exist in the sensitive population. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both PCa cell lines. A subset of these genes gave a gene expression profile in the resistant-like sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified potential 321 regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the PCa cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of sctotal RNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of PCa drug resistance, which provides the rationale to explore NUPR1 and its target genes to for reversal of docetaxel resistance.
2020-09-01 | GSE140440 | GEO
Project description:Nuclear Protein 1 (NUPR1) is a nuclear intrinsically disordered protein of 82 amino acids that plays an important role in stress response and in cancer development. The project was aimed at identifying binding partners of NUPR1 in MiaPaCa-2 cells, in control and after stress condition: glucose starvation during 24h. Lysates from MiaPaCa-2 cells (transfected with NUPR1-Flag or NUPR1-GFP) were used for immunoprecipitation, performed with agarose beads coated with anti-Flag or anti-GFP antibodies. After immunoprecipitation, the eluted proteins were analyzed by LC-MS/MS.
2022-07-29 | PXD035236 | Pride
Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management. To better understand the molecular mechanisms of NUPR1 gene action in ovarian HCC cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon NUPR1 suppression in HCC cells. We compared the gene expression of the previously selected shRNA-mediated NURP1-knockdown Hep3B clone against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the NUPR1-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2016-06-15 | E-GEOD-73521 | biostudies-arrayexpress
Project description:Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits is modest, also because its mechanism of action remains elusive, therefore, a better understanding of its molecular action and molecular targets are needed. On the basis of our previous studies, here, we investigated the role of the nuclear protein 1 (NUPR1) in HCC and its role in the context of sorafenib treatment. NUPR1 is a stress-inducible protein over-expressed in different malignancies, however, its role in HCC is not yet fully understood. We found that NUPR1, is over-expressed in 53% of primary human HCC samples. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibits cell growth, migration and invasion of HCC cells in vitro and tumorigenicity in vivo. Moreover, NUPR1 silencing influenced expression of target genes RelB and IER3. Unsurprisingly, RelB and IER3 knockdown also inhibited HCC cells viability, growth and migration. By gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as down-regulated gene nodes, and several genes known to be involved in hepatocarcinogenesis were also suppressed. In addition, we identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1 down-regulated gene. We also demonstrated that RUNX2 gene silencing inhibited HCC cells viability, growth, migration and increased cell sensitivity to sorafenib. Conclusion: We propose that NUPR1/RELB/IER3/RUNX2 pathway play pivotal role in hepatocarcinogenesis. The identification of NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.
2016-06-15 | GSE73521 | GEO
Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.
2016-05-25 | PXD001812 | Pride
Project description:ERG-mediated coregulator complex formation maintains androgen receptor signaling in prostate cancer
| PRJNA661225 | ENA
Project description:About one-third of oestrogen receptor alpha- positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen. Peptide and protein identification data set 1: Peptide identification from the MALDI-TOF/TOF data was carried out using the Paragon algorithm in the ProteinPilot 2.0 software package (Applied Biosystems) 46. Default settings for a 4800 instrument were used (i.e., no manual settings for mass tolerance was given). The following parameters were selected in the analysis method: iTRAQ 4plex peptide labelled as sample type, MMTS as alkylating agent of cysteine, trypsin as digesting enzyme, 4800 as instrument, gel based ID and Urea denaturation as special factors, biological modifications as ID focus, and thorough ID as search effort. Peptide identification from the Q-TOF data was carried out using the Spectrum Mill Protein Identification software (Agilent). Data was extracted between MH+ 600 and 4000 Da (Agilent's definition). Scans with the same precursor m/z 90 sec, 0.05 m/z matching with a minimum of 20 peaks in MS2 were merged. Peptide and protein identification data set 2: Proteome discoverer 1.3 with sequest-percolator was used for protein identification. Precursor mass tolerance was set to 10 ppm and for fragments 0.8 Da and 0.02 Da were used for detection in the linear iontrap and the orbitrap, respectively. Oxidized methionine and phosphorylation on S,T and Y was set as dynamic modifications, and carbamidomethylation, N-terminal 8plex iTRAQ, and lysyl 8plex iTRAQ as fixed modifications. Spectra were matched to ensembl 68 limited to human protein sequences, and results were filtered to 1% FDR.
2013-07-24 | PXD000281 | Pride