Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis.
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ABSTRACT:
SUBMITTER: Ding G
PROVIDER: S-EPMC7718645 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Project description:Speckle-type POZ protein (SPOP), as a cullin-based E3 ubiquitin ligase, has been identified as one of the most frequently mutated genes in prostate cancer (PCa). However, whether SPOP mutations contribute to metabolic reprogramming in PCa remains unknown. Here, integrated studies of transcriptomics and metabolomics as well as lipidomics were performed in matched PCa tumor (PCT) and adjacent non-tumor (ANT) tissues, followed by correlation analysis of SPOP mutations with altered metabolic pathways in SPOP-mutated PCa patients. Interestingly, transcriptomics profiling showed that all SPOP mutations (with 16.7% frequency, 11/66) occurred at the conserved residues in the substrate binding domain of meprin and TRAF homology (MATH). The results of integrated analysis indicated that three metabolic pathways, including tricarboxylic acid (TCA) cycle, fatty acid metabolism and glycerophospholipid metabolism, exhibited obvious upregulation in SPOP-mutated PCT tissues. Furthermore, both correlation analyses based on integrated data and cBioportal revealed that FH, ELOVL2 and ACADL genes might be involved in SPOP-mutation-related upregulation of these metabolic pathways. Taken together, our study provided new insights in understanding the relationship between metabolic pathways and SPOP mutations in PCa.
| S-EPMC5732708 | biostudies-literature
Project description:Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.
| S-EPMC4621745 | biostudies-literature
Project description:BackgroundProstate cancer (Pca) remains one of the leading adult malignancies. PTEN (Phosphatase and Tensin Homolog) mutant is the top common mutated genes in prostate cancer, which makes it a promising biomarker in future individualized treatment.MethodsWe obtained gene expression data of prostate cancer from TCGA (The Cancer Genome Atlas) database for analysis. We analyzed the DEGs (differentially expressed genes), and used online tools or software to analyze Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection.ResultsLatest TCGA data showed PTEN mutation in about 22% patients. 1736 DEGs in total were identified. Results of gene functional enrichment analyses showed that muscle contraction, negative regulation of growth and multiple metabolic progression were significantly enriched. GNG13, ACTN2, POTEE, ACTA1, MYH6, MYH3, MYH7, MYL1, TNNC1 and TNNC2 were the top ten hub genes. Patients with PTEN mutation showed relatively decreased mRNA expression level of PTEN. Survival analysis indicated the risk of disease recurrence in patients with PTEN mutation.ConclusionsOur findings suggested that PTEN mutation in prostate cancer may induce changes in a variety of genes and pathways and affect disease progression, suggesting the significance of PTEN mutation in individualized treatment of prostate cancer.
| S-EPMC6889628 | biostudies-literature
Project description:Prostate cancer (PrCa) is the most commonly diagnosed cancer in men in the world. Despite the fact that a large number of its genes have been investigated, its etiology remains poorly understood. Furthermore, most PrCa candidate genes have not been rigorously replicated, and the methods by which they biologically function in PrCa remain largely unknown.Aiming to identify key players in the complex prostate cancer system, we reconstructed PrCa co-expressed modules within functional gene sets defined by the Gene Ontology (GO) annotation (biological process, GO_BP). We primarily identified 118 GO_BP terms that were well-preserved between two independent gene expression datasets and a consequent 55 conserved co-expression modules within them. Five modules were then found to be significantly enriched with PrCa candidate genes collected from expression Quantitative Trait Loci (eQTL), somatic copy number alteration (SCNA), somatic mutation data, or prognostic analyses. Specifically, two transcription factors (TFs) (NFAT and SP1) and three microRNAs (hsa-miR-19a, hsa-miR-15a, and hsa-miR-200b) regulating these five candidate modules were found to be critical to the development of PrCa.Collectively, our results indicated that genes with similar functions may play important roles in disease through co-expression, and modules with different functions could be regulated by similar genetic components, such as TFs and microRNAs, in a synergistic manner.
| S-EPMC4258300 | biostudies-literature
Project description:Background: The molecular mechanism of tumorigenesis remains to be fully understood in breast cancer. It is urgently required to identify genes that are associated with breast cancer development and prognosis and to elucidate the underlying molecular mechanisms. In the present study, we aimed to identify potential pathogenic and prognostic differentially expressed genes (DEGs) in breast adenocarcinoma through bioinformatic analysis of public datasets. Methods: Four datasets (GSE21422, GSE29431, GSE42568, and GSE61304) from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) dataset were used for the bioinformatic analysis. DEGs were identified using LIMMA Package of R. The GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses were conducted through FunRich. The protein-protein interaction (PPI) network of the DEGs was established through STRING (Search Tool for the Retrieval of Interacting Genes database) website, visualized by Cytoscape and further analyzed by Molecular Complex Detection (MCODE). UALCAN and Kaplan-Meier (KM) plotter were employed to analyze the expression levels and prognostic values of hub genes. The expression levels of the hub genes were also validated in clinical samples from breast cancer patients. In addition, the gene-drug interaction network was constructed using Comparative Toxicogenomics Database (CTD). Results: In total, 203 up-regulated and 118 down-regulated DEGs were identified. Mitotic cell cycle and epithelial-to-mesenchymal transition pathway were the major enriched pathways for the up-regulated and down-regulated genes, respectively. The PPI network was constructed with 314 nodes and 1,810 interactions, and two significant modules are selected. The most significant enriched pathway in module 1 was the mitotic cell cycle. Moreover, six hub genes were selected and validated in clinical sample for further analysis owing to the high degree of connectivity, including CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK, and they were all correlated to worse overall survival (OS) in breast cancer. Conclusion: These results revealed that mitotic cell cycle and epithelial-to-mesenchymal transition pathway could be potential pathways accounting for the progression in breast cancer, and CDK1, CCNA2, TOP2A, CCNB1, KIF11, and MELK may be potential crucial genes. Further, it could be utilized as new biomarkers for prognosis and potential new targets for drug synthesis of breast cancer.
| S-EPMC6688090 | biostudies-literature
Project description:BackgroundThe pathophysiology of keloids is complex, and the treatment for keloids is still an unmet medical need. Our study is aimed at identifying the hub genes among the differentially expressed genes (DEGs) between normal skin tissue and keloids and key pathways in the development of keloids.Materials and methodsWe downloaded the GSE92566 and GSE90051 microarray data, which contain normal skin tissue and keloid gene expression data. GSE92566 was treated as a discovery dataset for summarizing the significantly DEGs, and GSE90051 served as a validation dataset. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome enrichment analysis, gene set enrichment analysis, and gene set variation analysis were performed for the key functions and pathways enriched in DEGs. Moreover, we also validated the hub genes identified from the protein-protein interaction network and predicted miRNA-hub gene interactions.Results117 downregulated DEGs and 204 upregulated DEGs in GSE92566 were identified. Extracellular and collagen-related pathways were prominent in upregulated DEGs, while the keratinization-related pathway was associated with downregulated DEGs. The hub genes included COL5A1, COL5A2, and SERPINH1, which were also validated in GSE90051.ConclusionThis study identified several hub genes and provided insights for the underlying pathways and miRNA-hub gene interactions for keloid development through bioinformatic analysis of two microarray datasets. Additionally, our results would support the development of future therapeutic strategies.
| S-EPMC8009712 | biostudies-literature
Project description:Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.
| S-EPMC4257137 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-21 | GSE88872 | GEO
Project description:Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.
| S-EPMC4209379 | biostudies-literature
Project description:The initiation of atopic dermatitis (AD) typically happens very early in life, but most of our understanding of AD is derived from studies on AD patients in adult. The aim of the present study was to identify gene signature speficic to pediatric AD comapred with adult AD. The gene expression profiles of four datasets (GSE32924, GSE36842, GSE58558, and GSE107361) were downloaded from the GEO database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed, and protein-protein interaction (PPI) network was constructed by Cytoscape software. Total 654 differentially expressed genes (DEGs) (394 up-regulated and 260 down-regulated) were identified in pediatric AD samples with adult AD samples as control. The up-regulated DEGs were significantly enriched in the migration and chemotaxis of granulocyte and neutrophil, while down-regulated DEGs were significantly enriched in biological adhesion. KEGG pathway analysis showed that up-regulated DEGs participated in chemokine signaling pathway while down-regulated DEGs participated in adherens junction, focal adhesion, and regulation of actin cytoskeleton. The top 10 hub genes GAPDH, EGFR, ACTB, ESR1, CDK1, CXCL8, CD44, KRAS, PTGS2, and SMC3 were involved in chemokine signaling pathway, cytokine-cytokine receptor interaction, interleukin-17 signaling pathway, and regulation of actin cytoskeleton. In conclusion, we identified DEGs and hub genes involved in pediatric AD, which might be used as therapeutic targets and diagnostic biomarkers for pediatric AD.
| S-EPMC7789805 | biostudies-literature