SIRT6 suppresses pancreatic cancer through control of Lin28b
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Kenneth Ross
PROVIDER: E-GEOD-79505 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample
2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress
Project description:The pioneer interactions between incoming viral RNA genomes and host proteins are crucial to infection and immune response. Until now, the ability to study these events was lacking. We developed VIR-CLASP (VIRal Cross-Linking And Solid-phase Purification) to characterize the earliest interactions between viral RNA and cellular proteins. We investigated the infection of human cells using Chikungunya virus (CHIKV) and Influenza A virus and identified hundreds of direct RNA-protein interactions. Here, we validate the biological impact of three protein classes that bind CHIKV RNA within minutes of infection. We find CHIKV RNA binds and hijacks the lipid-modifying enzyme FASN for pro-viral activity. We show that CHIKV genomes are N6-methyladenosine modified and that YTHDF1 binds and suppresses its replication. Finally, we find that the innate immune DNA sensor IFI16 associates with CHIKV RNA, reducing viral replication and maturation. Our findings have direct applicability to the investigation of potentially all RNA viruses.
2020-05-11 | PXD015863 | Pride
Project description:MicroRNAs are a class of short ~22 nucleotide RNAs predicted to regulate nearly half of all protein-coding genes, including many involved in basal cellular processes and organismal development. Although both increases and decreases in the levels of specific miRNAs have been shown to promote tumor development, a global reduction in miRNAs is commonly observed in various human tumors. However, complete loss has not been documented, suggesting an essential function for miRNAs in tumorigenesis. Here we present the finding that transformed or immortalized Dicer-null somatic cells can be isolated readily in vitro, maintain the characteristics of Dicer-expressing controls and remain stably proliferative. Furthermore, Dicer-null cells from a sarcoma cell line, though depleted of miRNAs, are competent for tumor formation. Hence, miRNA levels in cancer may be maintained in vivo by a complex stabilizing selection in the intratumoral environment. Small RNAs from tumor cell lines (murine sarcoma KrasG12D, p53 -/-) with and without Dicer (Dicer f/-, Dicer -/-) were analyzed.
2012-08-20 | E-GEOD-34825 | biostudies-arrayexpress
Project description:Breast Cancer (BC) has been associated with alterations in signaling through a number of growth factor and hormone regulated pathways. Mouse models for metastatic BC have been developed using oncoproteins that activate PI3K, Stat3 and Ras signaling. To determine the role of each pathway, we analyzed mouse mammary tumor formation when they were activated singly or pairwise. We used microarrays to detect differentially expressed genes in the KRas(G12D/+);CreT and R26(H1047R/+);KRas(G12D/+);CreT tumors Total RNA was extracted from tumors developed by Qiagen RNAeasy kit and hybridized on Affymetrix microarrays.
2015-09-16 | E-GEOD-73073 | biostudies-arrayexpress
Project description:Mice bearing a G12D activating mutation in Kras consistently develop lung adenocarcinomas in a manner analogous to humans. By performing small and large RNA sequencing on KrasG12D tumors from F1 hybrid mice we were able to identify genes and microRNAs differentially expressed in these tumor samples. Quantification of reads that cover single nucleotide polymorphisms that distinguish between the parental mouse strains enabled an analysis of allele specific expression and imprinting status in these tumors. mRNA and small RNA fractions of mouse lungs and lung adenocarcinomas were deep sequenced in triplicate
2013-12-09 | E-GEOD-43028 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE9070: Identification of Myc-regulated microRNAs in human P493 cells GSE9104: Identification of Myc-regulated microRNAs in mouse B cell lymphomas Keywords: SuperSeries Refer to individual Series
2010-05-22 | E-GEOD-9129 | biostudies-arrayexpress
Project description:To assess the transcriptional profile within tumours AhcreERTR26flEYFP/wt LSL Kras+/G12D animals were treated with diethylnitrosamine for 8 weeks prior to induction of the Kras allele with a single dose of β-naphthoflavone (20 mg/kg) and tamoxifen (0.25 mg). Subsequently, animals were treated with Sorafenib for 6 weeks. Gene expression array analysis was performed on 12 squamous cell carcinomas (SCCs) from 4 animals.
2016-07-08 | E-MTAB-4926 | biostudies-arrayexpress
Project description:Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing "leak" current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual SNr neurons. We discovered that SNr neurons express the sodium leak current, NaLCN and that SNr neurons lacking NaLCN have impaired spontaneous firing. RNA sequencing profiles from 87 GFP-positive GABAergic SNr neurons and 9 GFP-negative SNr cells were carried out. However only 80 samples that passed initial quality control and that were included in the data processing are represented in this record.
2016-05-13 | E-GEOD-78521 | biostudies-arrayexpress
Project description:Comparison of the transcriptomic profiles of Kras-miR802 WT and Kras-miR802 KO murine pancreas
2022-06-30 | E-MTAB-10411 | biostudies-arrayexpress