Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA982174 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24886950_1.fastq.gz | Fastqsanger.gz | |||
| SRR24886950_2.fastq.gz | Fastqsanger.gz | |||
| SRR24886951_1.fastq.gz | Fastqsanger.gz | |||
| SRR24886951_2.fastq.gz | Fastqsanger.gz | |||
| SRR24886952_1.fastq.gz | Fastqsanger.gz |
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Project description:Multiple myeloma (MM) is a blood disease characterized by the malignant accumulation of monoclonal plasma cells in the bone marrow. Among the pathological consequences of the MM, defects in osteogenesis characterized by osteolytic lesions, osteopenia, and pathologic fractures are frequently described. Che-1/AATF (Che-1) is a co-transcriptional factor involved in MM transformation and proliferation. Here, we show that Che-1 expression in MM contributes to maintaining low level of WWTR1 (TAZ), a transcriptional coactivator downstream of the Hippo-signaling pathway. We report that the miR-590-3p, deriving from the mRNA splicing of the EIF4H host gene, can target TAZ, contributing to downregulating its expression in MM. Furthermore, we demonstrate by in vivo and in vitro experiments that Che-1 transcriptionally induces EIF4H gene. We provide data to support that miR-590-3p is secreted by MM cells in vitro and in vivo and that can inhibit TAZ levels and the physiological transcriptional expression of osteogenic-related genes, in mesenchymal stem cells. Our findings unveil an unexplored novel Che-1/miR-590-3p/TAZ axis in MM tumorigenesis by providing a rationale to explore the therapeutic potential of metastatic bone lesions.
2024-04-10 | GSE234642 | GEO
Project description: Not available
| S-EPMC10997508 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in gene regulation and their dysregulation is associated with many diseases. In this study, we determined the expression and function of miR-590-3p in EOC. We found that miR-590-3p levels were higher in high-grade carcinoma when compared to low-grade or tumours with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in EOC patients than in subjects with benign gynaecological disorders. Transient transfection of miR-590-3p mimics, or stable transfection of mir-590, increased cell growth, migration, and invasion. In vivo studies revealed that mir-590 accelerated tumour growth and metastasis. Using a cDNA microarray, we identified Forkhead box A2 (FOXA2) and Versican (VCAN) as a top downregulated and a top upregulated gene, respectively, by mir-590. We showed that miR-590-3p targeted FOXA2 3’ UTR to suppress its expression. In addition, knockdown of FOXA2 by siRNAs or knockout of FOXA2 by CRISPR/Cas9 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, while knockout of FOXA2 increased, VCAN mRNA and protein levels and ChIP-qPCR revealed that FOXA2 binds to VCAN promoter. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumours and that high FOXA2/low VCAN mRNA levels in tumours were positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway.
2018-04-21 | GSE113440 | GEO
Project description:To identify the relevant targets of the selected miRNAs, we assessed global transcriptome changes by deep-sequencing total neonatal mouse cardiomyocyte RNA after transfection with hsa-miR-590-3p or hsa-miR-199a-3p Four condition experiment; one replicate per condition; mouse neonatal cardiomyocytes transfected with cel-miR-67, hsa-miR-590-3p and hsa-miR-199a-3p; samples collected 72 hours after transfection
2012-10-13 | E-GEOD-41538 | biostudies-arrayexpress
Project description:To identify the relevant targets of the selected miRNAs, we assessed global transcriptome changes by deep-sequencing total neonatal mouse cardiomyocyte RNA after transfection with hsa-miR-590-3p or hsa-miR-199a-3p
2012-10-13 | GSE41538 | GEO
Project description:Solid tumors are less oxygenated than normal tissues, and for this reason the cancer cells have developed several molecular mechanisms of adaptation to hypoxic environment. Moreover, his poor oxygenation is a major indicator of an adverse prognosis and leads resistance to standard anticancer treatment. Previous reports from this laboratory showed an involvement of Che-1/AATF (Che-1) in cancer cell survival under stress conditions, and on the basis of these observations, we hypothesized that Che-1 might have a role in the response of cancer cells to hypoxia. Methods: The human colon adenocarcinoma cell line HCT116 depleted or not for Che-1 by siRNA, was subjected to normoxic and hypoxic conditions to perform studies about the role of this protein in metabolic adaptation and cell proliferation. The expression of Che-1 under normoxia or hypoxia was detected using western blot assays; cell metabolism was assessed by NMR spectroscopy and functional assays. Further molecular studies were performed by RNA seq, qRT-PCR and ChIP analysis. Results: In this paper we report that Che-1 expression is required for the adaptation of the cells to hypoxia, playing and important role in metabolic modulation. Indeed, Che-1 depletion impacted on glycolysis by altering the expression of several genes involved in the response to hypoxia by modulating the levels of HIF-1alpha. Conclusions: These data demonstrate a novel player in the regulation of a HIF1alpha in response to hypoxia. We found that the transcriptional down-regulation of a members of E3 ubiquitin ligase family SIAH2 by Che-1, produces a failure in the degradation by the hydroxylase PHD3 with a decrease in HIF-1alpha levels during hypoxia.
2017-06-12 | GSE90599 | GEO
Project description:Che-1 is a RNA Polymerase II binding protein involved in the regulation of gene transcription. Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis. We have observed that Che-1 depletion sensitizes cells to chemotherapy. We used microarrays analysis to investigate classes of genes regulated by Che-1. Total RNA was extracted from control and Che-1 depleted HCT 116 cells 48 hours after transient transfection of siRNA.
2013-03-12 | E-GEOD-45009 | biostudies-arrayexpress
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100493 | GEO
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100646 | GEO
Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.
2021-06-07 | GSE100494 | GEO