<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The ERG-driven long non-coding RNA LINC00920 promotes cell proliferation and migration in prostate cancer cells by modulating FOXO activity through a direct interaction with 14-3-3ε"^^ . "This thesis describes LINC00920, a tumor-associated lncRNA identified in the transcriptome dataset of the International Cancer Genome Consortium-Early Onset Prostate Cancer (ICGC-EOPC) cohort. SiRNA-mediated knockdown of LINC00920 negatively affected proliferation, colony formation, and migration of PC-3 prostate cancer cells. Gene set enrichment analysis of microarray expression data revealed perturbation of pathways related to cell cycle, cell division, apoptosis, and cell movement. Focused pathway analysis of the top LINC00920-deregulated genes showed an inverse relationship between the lncRNA expression and FOXO signaling. Furthermore, as measured by qPCR, knockdown of LINC00920 activated canonical FOXO targets GADD45A, BCL2L11, and PMAIP1 while overexpression of the lncRNA reversed this effect.\r\n\r\nIn both The Cancer Genome Atlas-Prostate Adenocarcinoma (TCGA-PRAD) and ICGC-EOPC cohorts, LINC00920 positively correlated with ERG overexpression. The regulatory influence of ERG on the lncRNA was then established using cell line models of ERG overexpression, chromatin immunoprecipitation (ChIP) of ERG at the LINC00920 promoter, and promoter luciferase assays using wild-type and mutant promoter fragments.\r\n\r\nTo address the question of how LINC00920 elicits its associated cellular phenotypes with consideration to its presence across cytosolic, nucleoplasmic, and chromatin compartments, chromatin isolation by RNA purification (ChIRP) followed by high throughput DNA sequencing (ChIRP-seq) and mass spectrometry (ChIRP-MS) were conducted. At the chromatin level, LINC00920 was found primarily associating with heterochromatin regions. LINC00920 occupancy was also be detected in a subset of promoter regions and putative enhancer loci. Interestingly, the lncRNA trace across the mappable genome bore a resemblance to that of the enhancer-associated histone mark H3K4me1, suggesting a role for LINC00920 at enhancer elements. At the protein level, most of the identified LINC00920 interacting partners are well established RNA binding proteins typically associated with the process of transcription. Among the LINC00920-precipitated proteins robustly identified in three biological replicates were two 14-3-3 isoforms—14-3-3ε and 14-3-3ζ. Binding of LINC00920 to 14-3-3ε but not to 14-3-3ζ was validated by RNA immunoprecipitation (RIP) and affinity purification of recombinant 14-3-3ε on streptavidin beads using biotinylated LINC00920.\r\n\r\nFOXO activity is mitigated by AKT phosphorylation. FOXO phosphorylation triggers 14-3-3/FOXO complex formation, leading to nuclear exportation. Current results indicate the repressive influence of LINC00920 on FOXO signaling as well as the positive interaction between the transcript and 14-3-3ε. Considering these observations, a rational hypothesis emerged wherein LINC00920/14-3-3ε binding further stabilizes the 14-3-3ε/FOXO complex, resulting in a more efficient sequestration and consequent deactivation of FOXO.\r\n\r\nAltogether, this thesis contributes a novel mechanism for a tumor-associated lncRNA in the context of ERG-overexpressing prostate cancer cells. Beginning with the transcriptome analysis of the ICGC-EOPC cohort, and later the TCGA-PRAD dataset, LINC00920 was identified to be an ERG-driven transcript. Ultimately, molecular characterization of LINC00920 by ChIRP-MS has revealed its apparent role in modulating FOXO in conjunction with 14-3-3ε, resulting in reduced expression of a subset of tumor suppressive FOXO targets. Since ERG fusions are clonal events while PTEN deletions are subclonal, driving LINC00920 transcription could be a strategy, in part, for ERG-positive cells to alleviate the influence of an intact PTEN, paving the way for tumorigenesis."^^ . "2020" . . . . . . . "Arlou Kristina"^^ . "Angeles"^^ . "Arlou Kristina Angeles"^^ . . . . . . "The ERG-driven long non-coding RNA LINC00920 promotes cell proliferation and migration in prostate cancer cells by modulating FOXO activity through a direct interaction with 14-3-3ε (PDF)"^^ . . . "AA_Dissertation.pdf"^^ . . . "The ERG-driven long non-coding RNA LINC00920 promotes cell proliferation and migration in prostate cancer cells by modulating FOXO activity through a direct interaction with 14-3-3ε (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #27323 \n\nThe ERG-driven long non-coding RNA LINC00920 promotes cell proliferation and migration in prostate cancer cells by modulating FOXO activity through a direct interaction with 14-3-3ε\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .