Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome. Despite high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies, the role of Deubiquitylases (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. RNA-Seq analyses reveal a significant downregulation of MYC target genes upon OTUD6B and LIN28B downregulation.

PROVIDER: PRJEB45829 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	ERR10322751_1.fastq.gz	Fastqsanger.gz
	ERR10322751_2.fastq.gz	Fastqsanger.gz
	ERR10322752_1.fastq.gz	Fastqsanger.gz
	ERR10322752_2.fastq.gz	Fastqsanger.gz
	ERR10322753_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 54

Similar Datasets

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

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

Project description:Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome. Despite high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies, the role of Deubiquitylases (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.

| PRJEB46352 | ENA

The LIN28B/let-7 axis is a novel therapeutic pathway in Multiple Myeloma

Project description:MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof-of-principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC dependent cancers as well.

2015-07-21 | GSE71100 | 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

LIN28B and colon cancer

Project description:This SuperSeries is composed of the following subset Series: GSE26334: Expression data from LoVo colon cancer lines +/- constitutive LIN28B expression GSE26335: Expression data from xenograft tumors derived from LoVo colon cancer lines +/- constitutive LIN28B expression Refer to individual Series

2010-12-29 | E-GEOD-26336 | biostudies-arrayexpress

Expression data from LoVo colon cancer lines +/- constitutive LIN28B expression

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

Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a [Lin28b & Let7 transduction]

Project description:Mouse B cell precursors from fetal liver and adult bone marrow generate distinctive B cell progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for B lymphopoiesis, fetal “B-1” and adult “B-2”. Recently Lin28b was shown to be important for the switch between fetal and adult pathways; however, neither the mechanism of Lin28b action nor the importance of BCR signaling in this process was addressed. Here we report important advances in our understanding of the regulation of B 1/B-2 development. First, modulation of Let-7 in fetal Pro-B cells is sufficient to alter fetal B-1 development to produce B cells resembling the progeny of adult B-2 development. Second, intact BCR signaling is required for generation of B1a B cells from Lin28b-transduced bone marrow progenitors, supporting a requirement for ligand-dependent selection, as is the case for normal B1a B cells. Third, the VH repertore of Lin28b-induced bone marrow B1a B cells differs from that of normal B1a. Finally we identify the Arid3a transcription factor as a key target of Let-7, whose ectopic expression is sufficient to induce B-1 development in adult Pro-B cells and whose knockdown blocks B-1 development in fetal Pro-B cells. 2 individual sorts of bone marrow Pro-B cells 4 days after Lin28b retroviral transduction (and 2 sorts of empty vector control) and 2 individual sorts of fetal liver Pro-B cells 4 days after Let-7b retroviral transduction (and 2 sorts of empty vector controls).

2015-03-01 | E-GEOD-65534 | biostudies-arrayexpress

Expression data from xenograft tumors derived from LoVo colon cancer lines +/- constitutive LIN28B expression

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

Expression data from LoVo colon cancer lines +/- constitutive LIN28B expression

2010-12-29 | GSE26334 | GEO

LIN28B is overexpressed in specific subtypes of pediatric leukemia and regulates lncRNA H19 [K562]

Project description:The stem cell gene LIN28B was recently shown to be overexpressed in a foetal-like subgroup of juvenile myelomonocytic leukaemia. Given the involvement of LIN28B in a variety of solid paediatric cancers, we conducted a meta-analysis of LIN28B levels using publicly available gene expression data of 1361 paediatric leukaemia samples. Interestingly, this analysis revealed LIN28B overexpression in 102 childhood leukaemia patients (7.5%), suggesting oncogenic activity for LIN28B in the context of paediatric haematological diseases. As the mode of action of LIN28B during normal and malignant haematopoiesis remains largely unexplored, we subsequently analysed the transcriptional consequences of LIN28B modulation on normal and malignant haematopoietic cells and identified the long non-coding RNA (lncRNA) H19 as the first LIN28B-regulated lncRNA. K562 cells were retrovirally transduced with shRNA GN36578 against LIN28B and a shRNA-miR non-targeting control TRH1103 (both Transomic), selected with puromycin and hybridized on Agilent microarray.

2016-04-07 | E-GEOD-79980 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data