MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA492293 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7882630.fastq.gz | Fastqsanger.gz | |||
| SRR7882631.fastq.gz | Fastqsanger.gz | |||
| SRR7882632.fastq.gz | Fastqsanger.gz | |||
| SRR7882629.fastq.gz | Fastqsanger.gz |
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Project description:The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here, we report that MYC stimulates the transcription of DANCR, a long noncoding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell-cycle inhibitor p21 (CDKN1A) and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.Significance: These findings expand knowledge of how MYC drives cancer cell proliferation by identifying an oncogenic long noncoding RNA that is widely overexpressed in human cancers. Cancer Res; 78(1); 64-74. ©2017 AACR.
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Project description:Long noncoding RNAs regulating diverse cellular processes implicate in many diseases. Here, we report the identification of a novel long intergenic noncoding RNA, Linc-ASEN, expressed in prematurely senescent cells, that associates with UPF1 and represses cellular senescence by reducing p21 production transcriptionally and post-transcriptionally. The Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter. Moreover, the Linc-ASEN-UPF1 complex repressed p21 expression post-transcriptionally by lowering p21 mRNA stability in association with DCP1A. Accordingly, Linc-ASEN levels were found inversely correlated with p21 mRNA levels in tumor tissues from patient-derived xenograft mice, in various human cancer tissues, and in aged mice tissues. Our studies reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.
2019-09-24 | GSE128397 | GEO
Project description:Long noncoding RNAs regulating diverse cellular processes implicate in many diseases. Here, we report the identification of a novel long intergenic noncoding RNA, Linc-ASEN, expressed in prematurely senescent cells, that associates with UPF1 and represses cellular senescence by reducing p21 production transcriptionally and post-transcriptionally. The Linc-ASEN-UPF1 complex suppressed p21 transcription by recruiting Polycomb Repressive Complex 1 (PRC1) and PRC2 to the p21 locus, and thereby preventing binding of the transcriptional activator p53 on the p21 promoter. Moreover, the Linc-ASEN-UPF1 complex repressed p21 expression post-transcriptionally by lowering p21 mRNA stability in association with DCP1A. Accordingly, Linc-ASEN levels were found inversely correlated with p21 mRNA levels in tumor tissues from patient-derived xenograft mice, in various human cancer tissues, and in aged mice tissues. Our studies reveal that Linc-ASEN prevents cellular senescence by reducing the transcription and stability of p21 mRNA in concert with UPF1, and suggest that Linc-ASEN might be a potential therapeutic target in processes influenced by senescence, including cancer.
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Project description:To explore whether DANCR plays a role in nasopharyngeal carcinoma tumorigenesis, a RNA-seq analysis was performed to compare the gene expression profiles of DANCR siRNA and control groups.
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Project description:To capture endogenous DANCR transcripts, we designed and synthesized 11 5′ biotinylated 90-mer DNA oligonucleotides antisense that spanned the entire length of the target RNA DANCR. Pull-down proteins were separated by SDS-PAGE gel and stained with Fast Silver Stain Kit (Beyotime, China). Cell lysates were incubated with biotinylated DNA probes (10 pmol) and 50 μL of streptavidin-agarose beads (Invitrogen) for 1 hour. The proteins were precipitated and diluted in 50 μl of digestion buffer (8 M urea, 50 mM Tris-HCl pH 7.8), separated by SDS-PAGE gel electrophoresis and visualized by silver staining using the PAGE Gel Silver Staining Kit (Solarbio, Beijing, China) as the protocol described. Specific bands were excised for proteomics screening by mass spectrometry analysis (Tianjin Novogene Bioinformatic Technology, Tianjin, China).
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Project description:Long non-coding RNAs (lncRNAs) play crucial roles in regulating gene expression. Some are essential for organismal development and physiology, and they can contribute to diseases such as cancer. Whilst most lncRNAs exhibit little sequence similarity, conservation of lncRNA transcription relative to neighbouring protein-coding genes suggests potential functional significance. Nevertheless, most positionally equivalent lncRNAs are uncharacterized and it remains unclear whether they exert similar roles in distant species. Here, we identified syntenic melanoma-associated lncRNAs predicted to be components of the MITF gene regulatory network in human melanoma, with positionally equivalent transcripts in zebrafish. Among these, we prioritized Differentiation Antagonizing Non-Protein Coding RNA (DANCR), a cancer-associated lncRNA critical for maintaining somatic progenitor cells in human models, for functional investigation. Dancr is a multi-exonic, cytoplasmically enriched lncRNA transcribed from syntenic regions in the human and zebrafish genomes. MITF and c-MYC, key melanoma transcription factors, regulate human DANCR expression and melanoma patients with high DANCR display significantly decreased survival. DANCR is a melanoma oncogene that controls cancer-associated gene expression networks and promotes human melanoma cell proliferation and migration. Zebrafish dancr is dynamically expressed across multiple different cell types in the developing embryo, regulates genes involved in cell death, and is essential for embryonic development. Our work suggests that cancer-critical lncRNAs such as Dancr, expressed from similar regions in vertebrate genomes, may regulate related genes and processes involved in both embryonic development and tumorigenesis across species.
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