A transcriptome-wide divergence in protein translation scales with LIN28B expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE109423 | GEO | 2018/12/13
REPOSITORIES: GEO
Similar Datasets
Project description:A transcriptome-wide divergence in protein translation scales with LIN28B expression
| PRJNA430874 | ENA
Project description:We sought to elucidate the molecular mechanisms whereby LIN28B functions by comparing the gene expression profile of cells constitutively expressing LIN28B to empty vector controls. Accordingly, we performed microarray analysis on total RNA isolated from empty vector LoVo and LIN28B-expressing LoVo colon cancer cell lines. Constitutive LIN28B expression was achieved in the LoVo (ATCC #CCL-229) colon cancer cell line via retroviral transduction of MSCV-PIG-LIN28B. Contol = empty vector MSCV-PIG.
2010-12-29 | E-GEOD-26334 | biostudies-arrayexpress
Project description:We sought to elucidate functions of LIN28B and potential mechanisms whereby it may promote metastasis by comparing the gene expression profile of LIN28B metastases to primary tumors. Accordingly, we performed microarray analysis on total RNA isolated from empty vector tumors, LIN28B-LoVo tumors, and LIN28B-LoVo metastases Constitutive LIN28B expression was achieved in the LoVo (ATCC #CCL-229) colon cancer cell line via retroviral transduction of MSCV-PIG-LIN28B. xenografts were produced via injection of 1x106 cells subcutaneously into the rear flanks of nude mice. Microarrays were conducted on primary tumors from empty vector and LIN28B-expressing cells, as well as metastases derived from primary tumors constitutively expressing LIN28B. (Note: metastases did not occur with empty vector tumors)
2010-12-29 | E-GEOD-26335 | biostudies-arrayexpress
Project description:Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B subsequent to LIN28B phosphorylation. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. Binding of LIN28B at G1/S activates OTUD6B, which otherwise remains in a catalytically inactive state. As a consequence, stabilized LIN28B drives MYC expression via inhibition of let7 microRNAs, which in turn allows for a rapid transition of MM cells from G1 to S phase. Analyses of primary MM patient samples reveal a positive correlation of OTUDB6B expression with poor outcome, high MYC expression and MYC target gene induction, suggesting that high MYC levels in MM result from an activation of the OTUD6B-LIN28B nexus. Together, we here specify phosphorylation and cell cycle-dependent substrate binding as a means by which OTUD6B becomes activated to drive the G1/S transition via the LIN28B-MYC axis and nominate OTUD6B and LIN28B as actionable vulnerabilities in MM.
2022-10-12 | PXD027480 | Pride
Project description:The RNA binding protein Lin28b is highly expressed during embryogenesis but its expression declines in adult tissues, and aberrant expression of Lin28b is associated with tumour development and maintenance. Lin28b regulates the translation of several glycolytic and mitochondrial enzymes in order to enhance cellular metabolism and energy production. Lin28b is repressed by let-7 family microRNAs in a reciprocal negative regulatory circuitry where Lin28b supresses maturation of let-7. This circuitry obtains input from master regulators such as MYC that transcriptionally upregulates Lin28b, which is required for let-7 suppression and proliferation. Not much is known of how this circuitry is regulated through transcription of the let-7 microRNAs. Here we show that the transcription factor C/EBPβ-LIP induces aerobic glycolysis and mitochondrial respiration reminiscent to cancer cell metabolism. By integrating transcriptome, proteome and metabolic flux analysis we reveal that this LIP-induced metabolic reprogramming is dependent on Lin28b and that LIP enhances Lin28b expression through transcriptional repression of the let-7 microRNA family. Transgenic mice overexpressing LIP have reduced levels of let-7 in bone marrow, skin and spleen, which is associated with induction of Lin28b and hyperplasia. This study establishes LIP as a regulator of the let-7/Lin28b regulatory circuitry and we hypothesize that the LIP-controlled let-7/Lin28b regulation is involved in the de-regulation of tissue homeostasis and tumourigenesis.
2019-11-12 | PXD010095 | Pride
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:Aim: RNA binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Method: Here we describe a novel interplay between RBPsLIN28B and IMP1 in intestinal epithelial cells. Ribosome-profiling and RNA-sequencing identifies IMP1 as a principle nodefor gene expression regulation downstream of LIN28B. Results: In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild type or LIN28B-overexpressing mice enhancesthe regenerative response to irradiation. Conclusions: Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.
2018-12-27 | GSE115647 | GEO
Project description:Most colorectal cancers (CRCs) are moderately-differentiated or well-differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a novel post-transcriptional regulation mechanism via a previously unappreciated LIN28B-CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration and tumorigenesis. Our RNA-binding protein immunoprecipitation (RIP) assay revealed LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression results in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition. Chromatin immunoprecipitation (ChIP) sequence for CDX2 identified Alpha-Methylacyl-CoA racemase (AMACR) as a novel transcriptional target of CDX2 in the context of LIN28B overexpression. Overall, we demonstrate that LIN28B promotes CRC differentiation through CDX2-AMACR axis.
2021-01-28 | GSE165674 | 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. 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: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.
2016-04-01 | GSE79504 | GEO