Ontology highlight
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PROVIDER: PRJNA1210649 | ENA |
REPOSITORIES: ENA
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Project description:Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that usually occurs in adolescents between 15 and 19 years old and adults over 60 years old. Over the past 20 years, limited progress has been made in neoadjuvant chemotherapy and surgery aimed at curing OS. It is well known that alternative splicing (AS) changes caused by abnormal splicing factors contribute to tumor progression. But at present, there is a lack of extensive and in-depth AS research on OS. Gene expression analysis and AS analysis were performed on the sequencing data of 44 patients with osteosarcoma in order to construct a co-expression network among RNA-binding proteins, AS events, and AS genes in the whole genome. The gain or loss of functional osteosarcoma cell model was made, and the osteosarcoma phenotype was proved by in vitro and in vivo experiments. Interactive network analysis and enrichment analysis were carried out to define the internal mechanism.We screened the RBP of Karyopherin Subunit Alpha 2 (KPNA2), which was highly expressed in osteosarcoma cells and negatively correlated with patient survival. KPNA2 transports splicing factor Y-box Binding Protein 1 (YBX1) into the nucleus and promotes the proliferation, migration, and invasion of osteosarcoma. Using RNA-seq, we comprehensively screened and identified multiple AS events affected by YBX1. Specifically, YBX1 accelerates the degradation of ATP-dependent RNA helicase DDX3X (DDX3X) through the Nonsense-mediated decay (NMD) pathway by promoting the intron retention of the DDX3X gene, thus reducing the level of DDX3X protein. The changes in DDX3X in OS will affect significant changes in cell cycle-related proteins, including p53, p21, and AKT1. The KPNA2/YBX1 axis can regulate the stability of DDX3X mRNA and then affect the progress of the cell cycle. YBX1 promotes the proliferation, migration, and invasion of osteosarcoma by regulating the AS event of DDX3X. KPNA2/YBX1 axis activation is an important factor driving abnormal AS in OS. Importantly, we demonstrated that therapeutic targeting of the KPNA2/YBX1/DDX3X axis can inhibit OS proliferation and disease progression. It integrates the AS control of DDX3X into the progression of OS and represents potential prognostic biomarkers and targets of OS therapy.
2025-07-02 | GSE263410 | GEO
Project description:OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis
| PRJNA1329217 | ENA
Project description:FBXO32 drives pancreatic cancer progression
| PRJNA1083527 | ENA
Project description:Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous ‘self’ dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade. To assess the impact of DDX3X on the gene expression in the breast cancer, we stably depleted DDX3X in breast cancer MCF7 cells using a short hairpin RNA (shRNA)-mediated knockdown, and performed a genome-wide transcriptome analysis using a next-generation RNA deep sequencing.
2020-09-03 | GSE157323 | GEO
Project description:The ability of tumor cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. However, the signaling and nutritional potential of the stromal cell-secreted metabolites remains poorly understood. We identified a novel metabolic crosstalk between cancer associated fibroblasts (CAFs) and pancreatic cancer cells. We demonstrate that pancreatic CAFs regulate tumor cell metabolism through the secretion of acetate, which can be blocked by silencing ACLY in CAFs. Cancer cells present a unique dependence on CAF-derived acetate under acidosis. We further show that ACSS2 channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in the acidic microenvironment. Comparative H3K27ac ChIP-Seq and RNA-Seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We observed novel acetate/ACSS2-mediated acetylation of SP1 at lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished tumor burden in mouse models. Increased SAT1-mediated production of N1-acetylspermidine correlated with disease progression in the spontaneous tumor progression model and poor survival in cancer patients. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
2023-10-20 | MSV000093165 | MassIVE
Project description:The sex chromosome-encoded RNA helicases DDX3X and DDX3Y play important roles in RNA metabolism. Heterozygous mutations of DDX3X frequently occur in cancers and neurodevelopmental disorders which have strong sex biases. However, how different DDX3X variants impair cellular function in sex specific genetic background is not understood. Herein, we found that DDX3X variants with significantly impaired ATPase activities demixed into the shells of unique hollow condensates, the dynamics of which were further differentiated by the RNA binding affinities of the different DDX3X variants. Proteomic and imaging studies revealed that DDX3X variant condensates sequestered wild-type DDX3X, DDX3Y, and other proteins important for various signaling pathways. Intriguingly, wild-type DDX3X improved the dynamics of heterogenous variant/wild-type hollow condensates more than DDX3Y. These results suggest that DDX3X variants with distinct enzymatic and condensation propensities may interact uniquely with wild-type DDX3X or DDX3Y to cause sex-specific cellular impacts.
2022-11-26 | MSV000090789 | MassIVE
Project description:Individual nucleotide resolution cross-linking immunoprecipitation (iCLIP) detects protein-RNA binding sites at a single nucleotide resolution. We aimed to identify the transcripts directly bound to DDX3X and DDX54 in human breast cancer MCF7 cells and to characterize the site of interaction at a single nucleotide resolution.
2018-11-21 | E-MTAB-6230 | biostudies-arrayexpress
Project description:De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown. Here, we integrate transcriptomics, proteomics, and live imaging to demonstrate clinically diverse DDX3X missense mutations perturb neural development via distinct cellular and molecular mechanisms. Using mouse primary neural progenitors, we investigate four recurrently mutated DDX3X missense variants, from clinically severe (2) to mild (2). While clinically severe mutations impair neurogenesis, mild mutations have only a modest impact on cell fate. Moreover, expression of severe mutations leads to profound neuronal death. Using a proximity labeling screen in neural progenitors, we discover DDX3X missense variants have unique protein interactors. We observe notable overlap amongst severe mutations, suggesting common mechanisms underlying altered cell fate and survival. Transcriptomic analysis and subsequent cellular investigation highlights new pathways associated with DDX3X missense variants, including upregulated DNA Damage Response. Notably, clinically severe mutations exhibit excessive DNA damage in neurons, associated with aberrant cytoplasmic DNA:RNA hybrids and formation of stress granules. These findings highlight aberrant RNA metabolism and DNA damage in DDX3X-mediated neuronal cell death. In sum our findings reveal new mechanisms by which clinically distinct DDX3X missense mutations differentially impair neurodevelopment.
2025-01-06 | GSE279078 | GEO
Project description:Whole-genome sequencing recently identified recurrent missense mutations in the RNA helicase DDX3X in pediatric medulloblastoma (MB) and other tumors. The normal function of DDX3X is poorly understood, and the consequences of its cancer-associated mutations have not been explored. Here we used genomic, biochemical, cell biological, and animal modeling approaches to investigate normal DDX3X function and the impact of cancer-associated DDX3X mutations. Cross-linking immunoprecipitation–high-throughput sequencing (CLIPseq) analyses revealed that DDX3X binds primarily to ~1000 mature mRNA targets at binding sites spanning the full mRNA length; their enrichment in the coding regions suggests that DDX3X plays a role in translational elongation. The association of wild-type DDX3X with polysomes is consistent with this observation. Cancer-associated mutations result in loss of DDX3X from polysomes and accumulation of mutant DDX3X in stress granules (cytoplasmic accumulations of translationally arrested mRNAs). Mutation-dependent redistribution of DDX3X to stress granules is also observed in a Drosophila model system and in MB tumor cells from patients carrying DDX3X mutations. Importantly, mRNAs targeted by DDX3X are enriched in translation factors, suggesting that DDX3X regulates translation both directly and indirectly. Indeed, depletion of DDX3X by RNAi or over-expression of mutant DDX3X significantly impairs global protein synthesis. Ribosome profiling confirmed this observation and showed a 5’ bias in ribosomal occupancy, further confirming the role of DDX3X in translational elongation. Together, our data show that DDX3X is a key regulator of translation and that this function is impaired by cancer-associated mutations. Finally, we found that medulloblastoma-related mutant DDX3X can efficiently bind the wild-type form suggesting that mutant DDX3X could exert a dominant negative effect in vivo.
2016-05-20 | GSE59095 | GEO