Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1283949 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. ChIP-Seq experiments to examine H3K56ac histone modifications in murine PDAC cells that are Sirt6 wild type (WT), Sirt6 knock-out (KO), and Sirt6 KO cells engineered to express Sirt6 WT (Sirt6 KO + Sirt6 WT Restored).
2016-04-01 | E-GEOD-79503 | biostudies-arrayexpress
Project description:Genome wide copy number profiling of 20 PDAC cell lines to facilitate identification of novel tumor suppressor genes using an integrative genomics approach. Profiling of 20 commonly used PDAC cell lines
2012-11-01 | E-GEOD-41794 | biostudies-arrayexpress
Project description:Genome wide DNA methylation profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach Genome wide DNA methylation profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to identify novel tumor suppressor genes Bisulphite converted DNA from the 21 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip
2012-11-01 | E-GEOD-40097 | biostudies-arrayexpress
Project description:Genome wide expression profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach Genome wide expression profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach RNA from the 21 samples was converted to Cy3 labeled cRNA and hybridized to the array; arrays were processed with GenePix software and median array normalization was performed
2012-11-01 | E-GEOD-40098 | biostudies-arrayexpress
Project description:Genome wide copy number profiling of 20 PDAC cell lines to facilitate identification of novel tumor suppressor genes using an integrative genomics approach.
2012-11-01 | GSE41794 | GEO
Project description:Genome wide DNA methylation profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach Genome wide DNA methylation profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to identify novel tumor suppressor genes
2012-11-01 | GSE40097 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with no targeted or personalized therapeutics. PDAC cells reprogram their transcriptional and metabolic state to sustain their energetic needs in the nutrient-poor tumor microenvironment. Identifying molecular regulators of PDAC growth is a critical step towards an improved understanding of the disease and new therapeutic approaches. We employed in vivo CRISPR screening in an orthotopic PDAC model to identify transcription factors (TFs) and chromatin regulators (CRs) whose inhibition promotes aggressive growth of PDAC cells in vivo. The screening identified a previously uncharacterized ISL LIM homeobox 2 (ISL2) gene as a candidate tumor suppressor among some anticipated growth modulators. We confirmed that depletion of ISL2 leads to enhanced cell proliferation and tumor growth in vitro and in vivo. Conversely, the exogenous expression of ISL2 or CRISPR-mediated epigenetic upregulation of the endogenous loci led to reduced cell proliferation, supporting the hypothesis that ISL2 is a candidate tumor suppressor. Importantly, we find that ISL2 is a nuclear, chromatin-associated transcription factor that is epigenetically silenced through DNA methylation in a significant fraction of PDAC tumors. Critically, higher DNA methylation of ISL2 or its reduced expression correlates with poor patient survival. Mechanistically, ISL2 binds to thousands of genes, and its depletion increases antioxidant capacity, oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Critically, ISL2 depleted cells have heightened stemness potential, and we find PPAR as a critical modulator of cell proliferation in ISL2 depleted cells. Notably, ISL2 depleted cells are sensitive to small molecule inhibitors of mitochondrial complex I in vitro and in vivo. Collectively, these findings nominate ISL2 as a putative tumor suppressor candidate whose inactivation leads to an aggressive PDAC growth through increased mitochondrial metabolism and antioxidant capacity, which creates a potentially exploitable therapeutic vulnerability.
2022-04-04 | GSE180281 | GEO
Project description:Genome wide expression profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach Genome wide expression profiling of 20 PDAC cell lines and an immortalized non-malignant pancreatic duct cell line (HPDE) to facilitate identification of novel tumor suppressor genes using an integrative genomics approach
2012-11-01 | GSE40098 | GEO
Project description:Chromatin remodeling proteins are frequently dysregulated in human cancer, yet little is known about how they control tumorigenesis. Here, we uncover an epigenetic program mediated by the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) that is critical for suppression of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies. SIRT6 inactivation accelerates PDAC progression and metastasis via upregulation of Lin28b, a negative regulator of the let-7 microRNA. SIRT6 loss results in histone hyperacetylation at the Lin28b promoter, Myc recruitment, and pronounced induction of Lin28b and downstream let-7 target genes, HMGA2, IGF2BP1 and IGF2BP3. This epigenetic program defines a distinct subset representing 30-40% of human PDAC, characterized by poor prognosis and an exquisite dependence on Lin28b for tumor growth. Thus, we identify SIRT6 as an important PDAC tumor suppressor, and uncover the Lin28b pathway as a potential therapeutic target in a molecularlydefined PDAC subset. Small RNA-Seq experiments for PLKO and shLIN28B (three replicates each) in human Panc3.27 PDAC cells to identify miRNAs modulateed by LIN28B knockdown.
2016-04-01 | E-GEOD-79504 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.
2024-04-02 | MTBLS9418 | MetaboLights