Dataset Information

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

ABSTRACT: The INK4/ARF locus at chromosome 9p21 encoding p14ARF, p15INK4B and p16INK4A is a major tumor suppressor locus, constituting an important barrier for tumor growth. It is frequently inactivated in cancers, especially in urothelial carcinoma (UC). In addition to deletions and DNA hypermethylation, further epigenetic mechanisms might underlie its repression. One candidate factor is the long noncoding RNA ANRIL, which recruits Polycomb proteins (PcG) to regulate expression of target genes in cis and trans. We observed ANRIL overexpression in many UC tissues and cell lines mainly resulting from upregulation of 3'-truncated isoforms. However, aberrant ANRIL expression was neither associated with repression of INK4/ARF genes nor with proliferation activity or senescence. We wondered whether truncated ANRIL isoforms exhibit altered properties resulting in loss of function in cis. We excluded delocalization and performed RNA immunoprecipitation demonstrating interaction between full length or truncated ANRIL and PcG protein CBX7, but not SUZ12 of PRC2. Our data indicate that ANRIL in UC cells may not interact with PRC2, which is central for initializing gene repression. Thus, tissue-specific binding activities between ANRIL and PcG proteins may determine the regulatory function of ANRIL. In conclusion, ANRIL does not play a major role in repression of the INK4/ARF locus in UC.

SUBMITTER: Hoffmann MJ

PROVIDER: S-EPMC5932551 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Hoffmann Michèle J MJ Dehn Judith J Droop Johanna J Niegisch Günter G Niedworok Christian C Szarvas Tibor T Schulz Wolfgang A WA

Non-coding RNA 20151217 3

The INK4/ARF locus at chromosome 9p21 encoding p14ARF, p15INK4B and p16INK4A is a major tumor suppressor locus, constituting an important barrier for tumor growth. It is frequently inactivated in cancers, especially in urothelial carcinoma (UC). In addition to deletions and DNA hypermethylation, further epigenetic mechanisms might underlie its repression. One candidate factor is the long noncoding RNA ANRIL, which recruits Polyc ...[more]

PMID: 29861427

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Project description:Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management.

Dataset Information

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Publications

Truncated Isoforms of lncRNA ANRIL Are Overexpressed in Bladder Cancer, But Do Not Contribute to Repression of INK4 Tumor Suppressors.

Similar Datasets

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