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Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234642 | GEO | 2024/04/10

REPOSITORIES: GEO

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AATF/Che-1 localizes to paraspeckles and suppresses R-loops accumulation and interferon activation in Multiple Myeloma

Project description:We investigated the interactions of AATF/Che1 with paraspeckles complex in Multiple Myeloma(MM) cells by looking at its relationship with lncRNA NEAT1_1(NEAT1) and the essential paraspeckles proteins. By analyzing ChIP- and ChIRP-sequencing of MM cells, we assessed that the interaction between AATF/Che1 and NEAT1 occurs also onto DNA and detected the sites where they co-localize. To better characterize the interaction, we studied the effects of interfering AATF/Che1 or NEAT1 on co-localizing sites through ChIP-seq with NEAT1 interfered (GapmerNEAT1) and ChIRP-seq with AATF/Che1 interfered (siChe). We found that NEAT1 is essential in maintaining the paraspeckles complex onto those sites. Moreover, by exploring DRIP-seq data with siChe, we also detected that AATF/Che1 and NEAT1 localize on R-loops, RNA:DNA hybrid structure involved in DNA transcription and repair. A depletion of AATF/Che1 causes a further increase of those hybrid structures and the activation of the immune response in MM, in particular the interferon (IFN) activation. To further explore these findings, we performed RNA-seq with siChe and GapmerNEAT1 which confirm that AATF/Che-1 down-regulation induces a strong up-regulation of genes involved in IFN response.

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Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [ChIP-Seq]

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

Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [ATAC-Seq]

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Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [RNA-Seq]

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Transcript expression levels of neonatal mouse cardiomyocytes mock-transfected, or transfected with cel-miR-67, hsa-miR-590-3p or hsa-miR-199a-3p

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

Che-1 modulates the decision between cell cycle arrest and apoptosis by its binding to p53.

Project description:The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53- dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo to apoptosis in response to post-transcriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth-arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1+/- mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared to wild-type mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy.

2015-06-01 | GSE60267 | GEO

MicroRNA-590-3p promotes ovarian cancer growth and metastasis via a novel FOXA2-Versican pathway

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

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Project description:Multiple myeloma is a hematological neoplasm of plasma cells characterized by an abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and highly expressed in this malignancy. In order to better characterize its functions in this type of disease, we performed co-immunoprecipitation experiments coupled with a mass-spec analysis by using total MM Kms27 cell lysates. From this analysis we were able to identify more than 600 proteins significantly enriched in Che-1 precipitates. As expected from its role in ribosomal RNA maturation, the Che-1 interactome contains numerous proteins involved in pre-rRNA processing and several ribosomal proteins. Notably, among other proteins interacting with Che-1, we identified many essential components of the paraspeckle which play an important role in the regulation of gene expression.

2022-08-03 | PXD026659 | Pride

Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1α stabilization

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

Expression data from Che-1 (AATF) depleted HCT 116 cell line

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.

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