Identification of a silencer-like non-coding RNA transcribed from a region on the super-enhancer conferring B-cell lymphomagenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE324867 | GEO | 2026/06/30
REPOSITORIES: GEO
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Project description:Transcriptional profiling of LNCaP prostate cancer cells comparing control siRNA-treated LNCaP cells with LNCaP cells treated with siRNAs targeting Prostate Cancer Associated Transcript-1 (PCAT1), an uncharacterized long non-coding RNA. High-throughput sequencing of polyA+ RNA (RNA-Seq) in human cancer shows remarkable potential to identify both novel disease-specific markers for clinical uses and uncharacterized aspects of tumor biology, particularly non-coding RNA (ncRNA) species. To illustrate this approach, we employed RNA-Seq on a cohort of 102 prostate tissues and cells lines and found that aberrant expression profiles of novel tissue-specific ncRNAs distinguished benign, cancerous, and metastatic tumors. Among these, a novel prostate-cancer specific ncRNA (termed PCAT-1) defined a subset of aggressive cancers with low expression of the epigenetic regulator EZH2, a component of the Polycomb Repressive Complex 2 (PRC2) commonly upregulated in metastatic cancers. In vitro assays for core PRC2 genes indicated that the PRC2 complex directly binds and represses PCAT-1, and that the PCAT-1 transcript reciprocally binds PRC2, suggesting a regulatory feedback mechanism. Importantly, knockdown of PCAT-1 in cells with high levels of endogenous PCAT-1 transcript showed changes in cell proliferation and transcriptional regulation of several key biological processes, including cell cycle. Finally, we showed that ncRNA expression signatures, including PCAT-1, were effective for the non-invasive detection of prostate cancer, and that high ncRNA expression signature values correlate with high-grade histology. The findings presented herein establish the utility of RNA-Seq to comprehensively identify unannotated ncRNAs that define human disease states and characterize PCAT-1 as a novel regulator of cell proliferation mechanistically linked to PRC2 and contributory to translational clinical tests for prostate cancer. Two-condition experiment: Control-siRNA-treated versus PCAT1-siRNA-treated LNCaP cells. Biological replicates: 3 control replicates, 3 treatment replicates.
2011-07-27 | E-GEOD-29886 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new potential therapeutic targets. However, the non-coding genome of DLBCL remains unexplored. Here we show that active superenhancers (SEs) are highly and specifically hypermutated in 99% of DLBCL samples. Such aberrant somatic hypermutation (ASHM) displays signatures of Activation Induced Deaminase activity and is linked to genes encoding B cell developmental regulators and oncogenes. To elucidate the functional consequences of SE-ASHM, we explored two recurrent mutational hotspots identified in the SEs linked to the BCL6 and BCL2 proto-oncogenes, but unmutated in normal GC B cells. These mutations prevent the binding and transcriptional downregulation by the transcriptional repressors BLIMP1 and NR3C1, respectively. Genetic correction of selected mutations restored repressor DNA binding as well as target gene transcriptional repression. Notably, this led to counter-selection of cells harboring corrected alleles, indicating oncogenic dependency from the SE mutations. This pervasive SE mutational mechanism reveals a new major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.
2022-04-26 | GSE182214 | GEO
Project description:Transcriptional profiling of LNCaP prostate cancer cells comparing control siRNA-treated LNCaP cells with LNCaP cells treated with siRNAs targeting Prostate Cancer Associated Transcript-1 (PCAT1), an uncharacterized long non-coding RNA. High-throughput sequencing of polyA+ RNA (RNA-Seq) in human cancer shows remarkable potential to identify both novel disease-specific markers for clinical uses and uncharacterized aspects of tumor biology, particularly non-coding RNA (ncRNA) species. To illustrate this approach, we employed RNA-Seq on a cohort of 102 prostate tissues and cells lines and found that aberrant expression profiles of novel tissue-specific ncRNAs distinguished benign, cancerous, and metastatic tumors. Among these, a novel prostate-cancer specific ncRNA (termed PCAT-1) defined a subset of aggressive cancers with low expression of the epigenetic regulator EZH2, a component of the Polycomb Repressive Complex 2 (PRC2) commonly upregulated in metastatic cancers. In vitro assays for core PRC2 genes indicated that the PRC2 complex directly binds and represses PCAT-1, and that the PCAT-1 transcript reciprocally binds PRC2, suggesting a regulatory feedback mechanism. Importantly, knockdown of PCAT-1 in cells with high levels of endogenous PCAT-1 transcript showed changes in cell proliferation and transcriptional regulation of several key biological processes, including cell cycle. Finally, we showed that ncRNA expression signatures, including PCAT-1, were effective for the non-invasive detection of prostate cancer, and that high ncRNA expression signature values correlate with high-grade histology. The findings presented herein establish the utility of RNA-Seq to comprehensively identify unannotated ncRNAs that define human disease states and characterize PCAT-1 as a novel regulator of cell proliferation mechanistically linked to PRC2 and contributory to translational clinical tests for prostate cancer.
2011-07-28 | GSE29886 | GEO
Project description:Multiple myeloma (MM) ranks the second most prevalent haematological malignancy globally. Despite advancements in managing MM, it remains incurable due to the high genetic heterogeneity leading to treatment resistance and disease severity. One key drug resistance associated signalling pathway often hyperactivated in MM patients is the non-canonical NF- κB/p52 pathway. Additionally, dysregulated expression of various oncogenic long non-coding RNAs (lncRNAs) have been observed in MM. This study aims to examine the potential link between ncNF-κB activation and dysregulated lncRNA expression controlling the chemoresistance and oncogenic progression of MM. Using mutant MM cell lines as model system and omics data from MM patients, we identified a novel p52 regulated lncRNA enriched in high-risk MM patients. The lncRNA termed PLUM (PRC2 associated LncRNA regulating UPR in MM) is found to interact directly with PRC2 complex to mediate myeloma progression and chemoresistance. RACE (Rapid amplification of cDNA ends) analysis revealed PLUM exists in three main isoforms in drug resistant multiple myeloma cell lines (MMCLs), comprising 8 exons without coding potential. Functionally, PLUM exerts its oncogenic and drug resistance properties in vivo and in vitro via the activation of unfolded protein response (UPR) pathway. This is consistent with its elevated expression in VRd (Bortezomib- Lenalidomide-Dexamethasone) non-responsive MM patients. PLUM localizes predominantly in the nucleus where it interacts directly with the disordered region of EZH2 (489-494 aa residues) to facilitate formation of the PRC2 complex and EZH2 activity. Disruption of this interaction using steric antisense oligonucleotides (ASOs) re-sensitized MMCLs to drug treatment in vitro and in vivo, correlating with the loss of EZH2 H3K27 trimethylation activity and PRC2 complex stability. Finally, we demonstrate that PLUM-EZH2 regulates the expression of tumour suppressor genes, FOXO3 and ZFP36, to activate the UPR pathway and promote chemoresistance in MM. These findings indicate that ncNF-κB pathway regulated lncRNA PLUM is oncogenic, acting through the PRC2/FOXO3/ZFP36 axis to confer chemoresistance in MM.
2025-06-23 | PXD054586 | Pride
Project description:Croft2013 - GPCR-RGS interaction that compartmentalizes RGS activity
Through modelling studies, the classic quaternary complex (ligand-GPCR-G-RGS) has been extended to include an additional layer of regulation through GPCR-RGS interactions, which facilitate the compartmentalization of RGS activity into the plasma membrane and non-plasma compartments.
This model is described in the article:
A physiologically required G protein-coupled receptor (GPCR)-regulator of G protein signaling (RGS) interaction that compartmentalizes RGS activity.
Croft W, Hill C, McCann E, Bond M, Esparza-Franco M, Bennett J, Rand D, Davey J, Ladds G.
J Biol Chem. 2013 Sep 20;288(38):27327-42.
Abstract:
G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.
Author's comment on reproducing the plots:
To reproduce dose-response plots in the publication, the model is simulated with 12 different ligand concentrations (see parameter Ligand_conc).
For each ligand concentration, a single value corresponding to total amount of output must be obtained, by calculating the area under the curve of the trajectory of species z3, from time=0 to time=30.
These total output values are then used to build a dose-response plot (authors used GraphPad Prism).
Mutant strains are simulated with alternative parameter values or initial conditions specified in the Supplementary Material.
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2024-09-02 | BIOMD0000000479 | BioModels
Project description:Drug-tolerant “persister” tumor cells underlie the emergence of drug-resistant clones contribute to relapse and disease progression; thus, identifying actionable targets that disable persisters and mitigate relapse are a high priority need. Although the BCL2-targeting agent venetoclax (ABT-199) has shown promising responses in mantle cell and double hit B cell lymphomas, resistance often arises, yet mechanistically how this occurs is unclear. Here we report that ABT-199 resistance can evolve from persister clones that have selective deletions at 18q21 that involve the drug target BCL2 and the apoptotic regulators Noxa (PMAIP1) and TCF4. Notably, reprogramming of super enhancers (SE) in persisters contributes to resistance, where there is a selection for SE-directed overexpression of the apoptotic regulator BCL2A1 and oncogenic transcription factors IKZF1 and FOXC1. At the same time, the SE reprogramming confers an opportunity for overcoming ABT-199 resistance. An unbiased drug screen on a platform that recapitulates the lymphoma microenvironment revealed that persisters are vulnerable to inhibitors of transcription initiation and elongation, and especially so to inhibitors of cyclin-dependent kinase 7 (CDK7) that is essential for transcription initiation. Specifically, CDK7 loss or inhibition eliminated the persister phenotype by disabling SE-driven expression of BCL2A1, IKZF1 and FOXC1. Thus, the co-treatment of ABT-199 with CDK7 inhibitors blocked the evolution of drug resistance, and provoked tumor regression in models of mantle cell lymphoma (MCL) and double hit lymphomas (DHL) that overexpress both MYC and BCL2. Together, these findings establish loss of apoptotic regulators and an adaptive transcriptional response as drug resistance mechanisms in lymphoma, more importantly, establish a rationale for transcription inhibition-based combination strategies to prevent and overcome drug resistance in B cell malignancies toward BCL2 inhibitor.
2020-05-26 | PXD010193 | Pride
Project description:<p>Noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease and to reveal uncharacterized aspects of tumor biology. Here we discover 121 unannotated prostate cancer-associated ncRNA transcripts (PCATs) by <i>ab initio</i> assembly of high-throughput sequencing of polyA+ RNA (RNA-Seq) from a cohort of 102 prostate tissues and cells lines. We characterized one ncRNA, PCAT-1, as a prostate-specific regulator of cell proliferation and show that it is a target of the polycomb repressive complex 2 (PRC2). We further found that patterns of PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1-repressed target genes. Taken together, our findings suggest that PCAT-1 is a transcriptional repressor implicated in a subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes.</p>
| phs000443 | dbGaP
Project description:Immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma. However, ICB fails in many patients and has dangerous side effects. Rigosertib (RGS), a non-ATP-competitive small molecule RAS mimetic, has the potential to block oncogenic RAS-RAF-MEK-ERK and/or PI3K-AKT-mTOR signaling pathways. RGS treatment (300mg/kg) of melanoma tumor-bearing mice is well tolerated and results in ~50% inhibition of tumor growth as monotherapy and ~70% inhibition in combination with ICB. RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells, followed by immunogenic cell death, leading to an inflamed tumor microenvironment with enrichment of dendritic cells and activated CD8+ T cells. Highlights • RGS impairs melanoma tumor growth via direct killing and immunogenic cell death that promotes an inflamed tumor microenvironment. • RGS-induced tumor inhibition depends on the induction of CD40 expression on melanoma cells. • Combining RGS with αPD1+αCTLA4 improves tumor response. • Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor. Significance: A high CD40 expression level correlates with CD80, ICOS-L, beneficial type I T cell responses, and better survival in melanoma patients (cBioPortal database). Tumor CD40 levels are prognostic for therapeutic response to RGS and BRAF inhibitor (DepMap and Oncomine databases), and RGS induces CD40 expression in melanoma tumor cells. Our preclinical data support the therapeutic use of RGS plus αPD1+αCTLA4 in RAS/RAF/MEK and/or PI3K pathway-activated melanoma tumors and point to the need for clinical trials to determine the clinical benefit of RGS plus ICB for metastatic melanoma patients who do not respond to ICB alone.
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Project description:In this experiment we sought to identify region with differential PRC2, JARID2, and H3K27me3 occupancy in human induced pluripotent stem cell lines with silenced or expressed MEG3 locus to indirectly determine the effect of this ncRNA on PRC2 function. 8 hIPSC lines, 5 MEG3+ and 3 MEG3-; ChIP-seq for EZH2, JARID2, and H3K27me3. Some done in replicates.
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