Ontology highlight
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PROVIDER: PRJNA1222429 | ENA |
REPOSITORIES: ENA
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Project description: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.
2020-01-20 | GSE126940 | GEO
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
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
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
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
Project description:Despite a global decrease in colorectal cancer (CRC) incidence, the prevalence of early onset colorectal cancer (EOCRC), or those occurring in individuals before the age of 50, has been steadily increasing over the past several decades. When compared to later onset colorectal cancers (LOCRCs) in individuals over 50, our understanding of the genetic and molecular underpinnings of EOCRCs is limited. Here, we conducted transcriptomic analysis of patient-matched normal colonic segments and tumors to identify gene expression programs involved in carcinogenesis. Amongst differentially expressed genes, we found increased expression of the c-MYC (MYC) proto-oncogene and its downstream targets in tumor samples. We identify tumors with high and low differential MYC expression, and patients with high-MYC tumors were older and overweight or obese. We also detect elevated expression of the PVT1 long-non-coding RNA (lncRNA) in most tumors and find gains in copy number for both MYC and PVT1 gene loci in 35% of tumors evaluated. Our transcriptome analysis indicates that EOCRC can be sub-classified into groups based on differential MYC expression and suggests that MYC is a critical driver of most CRCs that develop in younger patients.
2022-09-06 | GSE196006 | GEO
Project description:CRISPRi targeting PVT1 specifically decrease PVT1-MYC interaction
2018-05-31 | GSE97585 | GEO
Project description:Long intergenic non-coding RNA (lincRNA) PVT1 is an oncogene known to be overexpressed in various types of cancer. PVT1 high expression is associated with increased prostate cancer (PCa) risk while androgen-independent PCa progression is correlated with increased androgen receptor (AR) expression. However, the mechanism of PVT1 and AR involvement in the development of prostate cancer is still unclear. Here, we tested the hypothesis that PVT1 participates along with AR and the methyltransferase EZH2 from the Polycomb repressive complex 2 in the repression of gene expression in LNCaP prostate cancer cells. Native RNA-binding proteins immunoprecipitation followed by quantitative PCR of co-precipitated RNAs (RIP-qPCR) revealed that in LNCaP, PVT1 lincRNA is associated both with AR (10 – 12 % of PVT1 input) and EZH2 (36 – 42 % of input) in the presence or absence of androgen. PVT1 knockdown in LNCaP in the presence of androgen increased the expression of 160 genes whose expression was repressed by androgen, including genes involved in regulation of cell differentiation, in inhibition of cell migration/invasion and in triggering apoptosis. Analysis by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) of the histone marks occupancy at the promoter region of the tumor suppressor gene NOV, one of the genes that had an increased expression upon PVT1 silencing, showed a significant epigenetic remodeling at its promoter and enhancer regions upon PVT1 knockdown. We provide evidence for a genome-wide transcriptional repressive role of PVT1 lincRNA on tumor suppressor genes in prostate cancer cells.
2021-01-19 | GSE133372 | GEO
Project description:MYC-PVT1 interaction is cell line specific
2018-05-31 | GSE97588 | GEO
Project description:PVT1 and MYC transcription is inversely correlated
2018-05-31 | GSE106197 | GEO