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LIN28B Regulates Transcription and Potentiates MYCN-induced Neuroblastoma in a let-7-independent Manner [ChIP-seq]

ABSTRACT: LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis at least in part through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type LIN28B, or a LIN28B mutant that is unable to bind and inhibit let-7, accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts and drives the distant metastases in vivo. Genome-wide ChIP-seq analysis and co-immunoprecipitation experiments show that LIN28B indirectly binds active gene promoters in neuroblastoma cells through an interaction with ZNF143 and activates the expression of downstream targets, including GSK3B and L1CAM, which are involved in neuronal cell adhesion and migration. These findings reveal an unexpected, let-7-independent function for LIN28B in transcriptional regulation during neuroblastoma pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138742 | GEO | 2020/07/22

REPOSITORIES: GEO

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LIN28B Regulates Transcription and Potentiates MYCN-induced Neuroblastoma in a let-7-independent Manner [RNA-seq]

Project description:LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis at least in part through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type LIN28B, or a LIN28B mutant that is unable to bind and inhibit let-7, accelerates the onset and increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts and drives the distant metastases in vivo. Genome-wide ChIP-seq analysis and co-immunoprecipitation experiments show that LIN28B indirectly binds active gene promoters in neuroblastoma cells through an interaction with ZNF143 and activates the expression of downstream targets, including GSK3B and L1CAM, which are involved in neuronal cell adhesion and migration. These findings reveal an unexpected, let-7-independent function for LIN28B in transcriptional regulation during neuroblastoma pathogenesis.

2020-07-22 | GSE138741 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RIP-Seq)

Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher adenine/uridine (AU)-content, and depletion of transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.

2022-09-30 | GSE183336 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (Polysome sequencing)

2022-09-30 | GSE183335 | GEO

LIN28B alters ribosomal dynamics to promote metastasis in MYCN-driven malignancy (RNA-Seq)

Project description:High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we show that LIN28B expression is associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7 independent enrichment of transcripts encoding components of the translational and ribosomal apparatus, particularly those with higher Adenine/Uridine (AU)-content, and depletion of GC-rich transcripts of neuronal developmental programs. We further show that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrate that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a post-transcriptional driver of the metastatic phenotype.

2022-09-30 | GSE158320 | GEO

RNA-seq transcriptomic analysis of mouse sympathetic neuroblasts and adrenal chromaffin cells

Project description:Adrenal chromaffin cells and sympathetic neuron are derived from neural crest precursors and both cell types can give rise to childhood cancer, neuroblastoma. However only limited is known about the mechanism of their development. Better understanding of their transcriptomic profiles during development could gives an insight into the cell fates acquisition as well as the origin of neuroblastoma. Yellow fluorescent protein expressing sympathetic neuroblasts and adrenal chromaffin cells were isolated from E12.5 TH-IRES-Cre;ROSA26-EYFP mouse embryos by fluorescence-activated cell sorting. Transcriptomic profiles of sympathetic neuroblasts and adrenal chromaffin cells from embryonic age (E)12.5 TH-IRES-Cre;ROSA26-EYFP mice were generated by RNA sequencing, in four paired biological replicates.

2019-05-24 | E-MTAB-7086 | biostudies-arrayexpress

A multi-omics approach reveals enrichment in metabolites involved in the regulation of the glutathione pathway in LIN28B-dependent cancer cells.

Project description:The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study contributes valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions. The study explores how the ectopic induction of the LIN28B oncogene affects the overall gene expression pattern in the SH-SY5Y neuroblastoma tumor cell line. The Tet-on system was employed in the investigation. This study reveals that escalating LIN28B expression significantly impacts neuroblastoma cell metabolism, suggesting a disruption in redox balance.

2024-02-14 | GSE252806 | GEO

Array comparative genomic hybridization of spheres derived from TH-MYCN (hemizygote) mice [Agilent-027441]

Project description:It has been already reported that there are undifferentiated/proliferating neuroblasts in the postnatal sympathetic ganglia in TH-MYCN mice, a neuroblastoma model. We established suitable spheroid culture condition that selectively isolates undifferentiated neuroblasts from superior mesenteric ganligon (SMG) of TH-MYCN mice. In order to investigate the chromosomal alterations (gains or losses) of spheres derived from TH-MYCN mice, we carried out array comparative genomic hybridization. We investigated whether chromosomal alterations occured during early neuroblastoma tumorigenesis in TH-MYCN mice.

2017-04-01 | GSE89740 | GEO

C/EBPβ-LIP regulates the let-7/Lin28b circuit to induce cancer-type metabolic reprogramming

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

The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma

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

LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3

Project description:The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unravel a novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2 and LoVo) with either knockdown or overexpression of LIN28B, we identified Claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and post-transcriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA-sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B-CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by post-transcriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.

2023-09-14 | GSE234513 | GEO

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