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P53 activates the long noncoding RNA Pvt1b to inhibit Myc and suppress tumorigenesis

ABSTRACT: P53 activation in response to cellular stress has long been known to result in downregulation of c-myc, a gene that is frequently overexpressed in cancer due to its role in promoting cellular proliferation. However, the mechanism underlying this p53 dependent myc repression is poorly understood. Here we report p53 regulation of the lncRNA PVT1, a neighboring myc gene which is upregulated following p53 activation via p53 binding to a canonical p53 response element (p53RE) in the first intron of PVT1. Specifically, we find that p53 activation results in induction of an isoform of PVT1 initiated from an alternative first exon, which we have termed PVT1alt. When the PVT1 p53RE is mutated and PVT1alt induction is inhibited, we observe increased levels of myc mRNA in cells undergoing DNA damage or oncogenic stress and corresponding increases in cellular proliferation. The PVT1alt RNA is required for this p53-dependent myc repression, suggesting a important growth suppressive role for this lncRNA in the p53 response. Our study reveals a novel mode of myc regulation in cis by an alternative lncRNA isoform, providing insight into an important mechanism of crosstalk between the p53 and myc transcriptional networks.

ORGANISM(S): Mus musculus

PROVIDER: GSE126940 | GEO | 2020/01/20

REPOSITORIES: GEO

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p53 activates the long noncoding RNA Pvt1b to inhibit Myc and suppress tumorigenesis

Project description:The tumor suppressor p53 transcriptionally activates target genes to suppress cellular proliferation during stress. p53 has also been implicated in the repression of the proto-oncogene Myc, but the mechanism has remained unclear. Here, we identify Pvt1b, a p53-dependent isoform of the long noncoding RNA (lncRNA) Pvt1, expressed 50 Kb downstream of Myc, which becomes induced by DNA damage or oncogenic signaling and accumulates near its site of transcription. We show that production of the Pvt1b RNA is necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus. Inhibition of Pvt1b increases Myc levels and transcriptional activity and promotes cellular proliferation. Furthermore, Pvt1b loss accelerates tumor growth, but not tumor progression, in an autochthonous mouse model of lung cancer. These findings demonstrate that Pvt1b acts at the intersection of the p53 and Myc transcriptional networks to reinforce the anti-proliferative activities of p53.

2020-01-20 | GSE142772 | GEO

Long non-coding RNA PVT1 is overexpressed in cutaneous squamous cell carcinoma and exon 2 is critical for its oncogenicity

Project description:Background Cutaneous squamous cell carcinoma (cSCC) is one of the most common and fastest increasing forms of cancer worldwide with metastatic potential. Long non-coding RNAs (lncRNAs) are a group of RNA-molecules with essential regulatory functions for both physiological and pathological processes. Objectives To investigate the function and mode of action of lncRNA plasmacytoma variant translocation 1 (PVT1) in cSCC. Methods The expression level of PVT1 was quantified in healthy skin, benign skin diseases and cSCCs by qRT-PCR and single molecule in situ hybridization. The function of PVT1 in cSCC was investigated both in vivo (tumour xenograft) and in vitro (competitive cell growth assay, EdU-incorporation assay, colony formation assay and tumour spheroid formation assay) by CRISPR-Cas9-mediated PVT1 or PVT1 exon 2 knockout and by locked nucleic acid (LNA) GapmeR-mediated PVT1-knockdown. RNAseq-analysis was conducted to identify genes and processes regulated by PVT1. Results We identified PVT1 as a lncRNA upregulated in cutaneous squamous cell carcinoma in situ (cSCCIS) and cSCC and associated with oncogenic phenotype of cSCC. The increased expression of PVT1 in cSCC was regulated by MYC. Both CRISPR-Cas9-deletion of the entire PVT1 locus and LNA GapmeR-mediated knockdown of PVT1-transcript impaired malignant behaviour of cSCC cells which suggested that PVT1 is an oncogenic transcript in cSCC. Furthermore, knockout of PVT1 exon 2 inhibited cSCC tumour growth both in vivo and in vitro demonstrating that exon 2 is a critical element for the oncogenic role of PVT1. Mechanistically, we show that PVT1 is localized in the cell nucleus and acts as a suppressor of cellular senescence by inhibiting CDKN1A expression and preventing cell cycle arrest. Conclusions Our study reveals a previously unrecognized role for exon 2 of PVT1 in its oncogenic role and that PVT1 suppresses cellular senescence. PVT1 may be a biomarker and therapeutic target in cSCC.

2023-11-30 | GSE235606 | GEO

N6-methyladenosine Modification of lncRNA Pvt1 Governs Epidermal Stemness

Project description:Dynamic chemical modifications of RNA represent novel and fundamental mechanisms that regulate stemness and tissue homeostasis. Rejuvenation and wound repair of mammalian skin are sustained by epidermal progenitor cells, which are localized within the basal layer of the skin epidermis. N6-methyladenosine (m6A) is one of the most abundant modifications found in eukaryotic mRNA and lncRNA (long non-coding RNA). In this report, we survey changes of m6A RNA methylomes upon epidermal differentiation, and identify Pvt1, a lncRNA whose m6A modification is critically involved in sustaining stemness of epidermal progenitor cells. With genome-editing and a mouse genetics approach, we show that ablation of m6A methyltransferase or Pvt1 impairs the self-renewal and wound healing capability of skin. Mechanistically, methylation of Pvt1 transcripts enhances its interaction with MYC and stabilizes the MYC protein in epidermal progenitor cells. Our study presents a global view of epitranscriptomic dynamics that occur during epidermal differentiation and identifies the m6A modification of Pvt1 as a key signaling event involved in skin tissue homeostasis and wound repair.

2021-02-01 | GSE165912 | GEO

Gene expression changes associated with knockdown of lncRNA PVT1 in ovarian cancer cell line SK-OV3

Project description:lncRNA PVT1 is an emerging lncRNA of significance in cancer due to alterations in both the RNA and genomic locus in multiple cancers and its established relationship to the oncogene MYC. Several recent studies have documented potential important roles for the lncRNA in ovarian cancer. Herein RNA sequencing was performed to determine the impact of PVT1 on global gene expression by performing RNA sequencing in SK-OV3 cells after silencing PVT1 (siPVT1) of cells grown upon transient knockdown of the lncRNA PVT1. SK-OV3 cells were cultured to 50% confluence in 6 well plates. Pooled siRNA’s to human PVT1 or non targeting control siRNA’s from Dharmacon were used to transfect SK-OV3 cells for 48 hrs in full serum media carefully maintaining cell confluence to not exceed approximately 80%. This was followed by RNA extraction and verification of knockdown using primers to PVT1 followed by sequencing. We find that 450 protein coding genes were differentially expressed between control (siControl) and siPVT1 cells with 50 additional found to be non-protein coding. The top 50 differentially expressed genes include 12 that were downregulated by siPVT1 and 32 that were upregulated. Several pathways associated with metabolic and stress processes, ribosome biogenesis and ncRNA processing were altered based on GO pathway analysis. Additional pathways included pathways associated with cell motility and differentiation.

2022-07-06 | GSE185933 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis for H3K27ac mediated chromatin conformation capture of Wild Type and PVT1 Knockdown by CRISPRi in MDA-MB-231 human breast cancer cell line

Project description:CRISPRi targeting PVT1 specifically decrease PVT1-MYC interaction

2018-05-31 | GSE97585 | GEO

Transcription profiling of mouse lymphoid neoplasia shows changes in processing of 3 prime-UTR characterize clinically distinct tumor types

Project description:We used a novel probe-level microarray analysis, revealing connections between mRNA processing and lymphoid neoplasia, in a mouse leukemia model. Characteristic differences in mRNA processing, primarily in the 3’-untranslated region, distinguished histologically similar tumor subtypes with different survival characteristics. Gene sets with specific processing in each tumor subtype defined signatures useful for tumor subclassification, as demonstrated by internal cross-validation with up to 80% discrimination accuracy. A combination of mRNA expression and sequence analysis suggested that differences in isoform abundance likely arose from both alternative polyadenylation and differential degradation. Experiment Overall Design: 5 types of samples were analyzed with multiple biological replicates. Progenitor B-cells, mature B-cells were the control. LPC, APC, APN were the tumor cells. LPC (Lig4/P53 deficient cells developed pro-B lymphoma with c-myc amplification), APC (Artemis/P53 deficient cells developed pro-B lymphoma with c-myc amplification), APN (Artemis/P53 deficient cells developed pro-B lymphoma with N-myc amplification)

2009-10-16 | E-GEOD-15808 | biostudies-arrayexpress

Transcriptional response to serum stimulation of Rat1 fibroblasts in the presence or absence of the Myc interfering molecule termed Omomyc.

Project description:Myc is a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers. How to target Myc for cancer therapy is unclear, given its involvement in a variety of key functions in healthy cells. We used microarrays to capture the cellular transcriptional response to Omomyc – a Myc interfering molecule acting at the level of protein protein interactions that demonstrated a remarkable therapeutic efficacy in transgenic mouse cancer models. We found that Omomyc differently affects Myc induced gene repression and activation, channelling the Myc interactome activity to repression.

2010-12-21 | GSE25039 | GEO

p53-dependent effects of DNA double-strand breaks on chromatin accessibility

Project description:We used ATAC-seq to detect changes in chromatin accessibility and nucleosome positioning around the MYC gene during the DNA double-strand break response in human cells and the dependence of these changes on p53. We found that, in the region ~50 kb downstream of MYC where p53 binds strongly, chromatin accessibility as measured by ATAC-seq fragment density increased during the DNA DSB response, corresponding to the removal of a single nucleosome. These results are consistent with increased accessibility of a distal regulatory element at this locus that is dependent on DNA damage and p53 expression. At the MYC promoter region there is a p53-dependent decrease in chromatin accessibility in response to DSBs, even in the absence of a direct p53 binding site near the region. While both the P1 and P2 promoters of MYC are relatively free of nucleosomes in MCF-7 sh-p53 cells, both promoters are occluded in cells expressing WT levels of p53, with an increase of nucleosomal occlusion in response to DNA damage. This supports the hypothesis that MYC repression during the DNA DSB response results from nucleosomal occlusion of both the P1 and P2 promoters.

2017-08-02 | GSE101736 | GEO

Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo [DNAse-Seq]

Project description:The tumor suppressor p53 is a transcription factor that coordinates the cellular response to DNA damage. Here we provide an integrated analysis of p53 genomic occupancy and p53-dependent gene regulation in the splenic B and non-B cell compartments of mice exposed to whole-body ionizing radiation, providing insight into general principles of p53 activity in vivo. In unstressed conditions, p53 bound few genomic targets; induction of p53 by ionizing radiation increased the number of p53 bound sites, leading to highly overlapping profiles in the different cell types. Comparison of these profiles with chromatin features in unstressed B cells revealed that, upon activation, p53 localized at active promoters, distal enhancers, and a smaller set of unmarked distal regions. At promoters, recognition of the canonical p53 motif as well as binding strength were associated with p53-dependent transcriptional activation, but not repression, indicating that the latter was most likely indirect. p53-activated targets constituted the core of a cell type-independent response, superimposed onto a cell type-specific program. Core response genes included most of the known p53-regulated genes, as well as many new ones. Our data represent a unique characterization of the p53-regulated response to ionizing radiation in vivo. Mapping accessible chromatin regions in splenic B cells

2015-08-24 | E-GEOD-71177 | biostudies-arrayexpress

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

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