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Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3 [Affymetrix Human Gene 2.0 ST]

ABSTRACT: Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a critical prosurvival function in colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the promoters of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90084 | GEO | 2017/05/31

SECONDARY ACCESSION(S): PRJNA354547

REPOSITORIES: GEO

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Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3 [Illumina HumanHT-12 V4.0]

Project description:Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a critical prosurvival function in colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the promoters of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

2017-05-31 | GSE90085 | GEO

Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3

Project description:Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3

| PRJNA354384 | ENA

Transcription profiling of HeLa cells expressing GFP-tagged chicken matrin 3

Project description:We have found that exogenous expression of matrin 3 in chicken DT40 cells and human HeLa cells suppressed expression of endogenous matrin 3 at mRNA level. To find other genes showing decreased expression by exogenous matrin 3, gene expression profiles of wild-type HeLa cells and HeLa cells expressing GFP-tagged chicken matrin 3 were compared.

2007-03-10 | E-MEXP-1032 | biostudies-arrayexpress

Required Enhancer: Matrin-3 Structure Interactions for Homeodomain Transcription Programs

2014-08-03 | GSE58009 | GEO

Required Enhancer: Matrin-3 Structure Interactions for Homeodomain Transcription Programs

Project description:Study of the POU-homeodomain transcription factor, has revealed that, binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture is a key event in effective activation of the Pit1-regulated enhancer / coding gene transcriptional program. All ChIP-seq(s) were designed to understand the unique features, associated molecular mechanisms and functions of Matrin3 in the Homeodomain transcription study. Gro-seq Samples are used to detect gene expression between knockdown control and knockdown two key factors in our study.

2014-08-03 | E-GEOD-58009 | biostudies-arrayexpress

ALS Associated Mutations in Matrin 3 Alter Protein-Protein Interactions and Impede mRNA Nuclear Export

Project description:Mutations in Matrin 3 have recently been linked to ALS, though the mechanism of disease in these patients is still unknown. To define the protein interactome of wild-type and ALS-linked MATR3 mutations, we performed immunoprecipitation followed by mass spectrometry experiments in NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin in mRNA transport centered around proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and the mRNA of ALS linked proteins TDP-43 and FUS. Our findings demonstrate the first pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS.

2017-11-15 | PXD007710 | Pride

CDK4/6 inhibitors induce repication stress to cause long-term cell cycle withdrawal

Project description:CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are licenced to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a temporary cell cycle arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that chemotherapeutics that cause replication stress also induce sensitivity to CDK4/6 inhibition.

2021-12-20 | PXD023435 | Pride

LncRNA LIMp27 regulates the DNA damage response through p27 in p53-defective cancer cells

Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.

| MSV000090292 | MassIVE

CAPG silencing promotes CRC cell apoptosis and ferroptosis via P53 pathway

Project description:Colorectal cancer (CRC) is the third most common cancer in the world and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for colorectal cancer. Here, we report that Capping Actin Protein, Gelsolin Like (CAPG), a protein involved in actin related movement, is significantly overexpressed in human CRC tissues, and that expression levels are inversely correlated with overall survival. CAPG knockdown CRC cell lines inhibited cell proliferation, blocked cell cycle in G1 phase, increased apoptosis rate and promoted the occurrence of ferroptosis. RNA-seq data suggested that CAPG silencing promotes cell cycle arrest, apoptosis, and ferroptosis by activating the P53 pathway. Therefore, CAPG has potential to serve as a prognostic marker as well as a cancer therapy target in the future.

2023-06-11 | GSE234395 | GEO

Transcription profiling of human Ls174T CRC cells with induced of dnTCF-4

Project description:The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1) transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.

2005-09-02 | E-SMDB-1723 | biostudies-arrayexpress

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