Dataset Information

PRC2 is dispensable for HOTAIR-mediated transcriptional repression.

ABSTRACT: Long non-coding RNAs (lncRNAs) play diverse roles in physiological and pathological processes. Several lncRNAs have been suggested to modulate gene expression by guiding chromatin-modifying complexes to specific sites in the genome. However, besides the example of Xist, clear-cut evidence demonstrating this novel mode of regulation remains sparse. Here, we focus on HOTAIR, a lncRNA that is overexpressed in several tumor types and previously proposed to play a key role in gene silencing through direct recruitment of Polycomb Repressive Complex 2 (PRC2) to defined genomic loci. Using genetic tools and a novel RNA-tethering system, we investigated the interplay between HOTAIR and PRC2 in gene silencing. Surprisingly, we observed that forced overexpression of HOTAIR in breast cancer cells leads to subtle transcriptomic changes that appear to be independent of PRC2. Mechanistically, we found that artificial tethering of HOTAIR to chromatin causes transcriptional repression, but that this effect does not require PRC2. Instead, PRC2 recruitment appears to be a consequence of gene silencing. We propose that PRC2 binding to RNA might serve functions other than chromatin targeting.

SUBMITTER: Portoso M

PROVIDER: S-EPMC5391141 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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PRC2 is dispensable for <i>HOTAIR</i>-mediated transcriptional repression.

Portoso Manuela M Ragazzini Roberta R Brenčič Živa Ž Moiani Arianna A Michaud Audrey A Vassilev Ivaylo I Wassef Michel M Servant Nicolas N Sargueil Bruno B Margueron Raphaël R

The EMBO journal 20170206 8

Long non-coding RNAs (lncRNAs) play diverse roles in physiological and pathological processes. Several lncRNAs have been suggested to modulate gene expression by guiding chromatin-modifying complexes to specific sites in the genome. However, besides the example of Xist, clear-cut evidence demonstrating this novel mode of regulation remains sparse. Here, we focus on <i>HOTAIR</i>, a lncRNA that is overexpressed in several tumor types and previously proposed to play a key role in gene silencing th ...[more]

PMID: 28167697

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Project description:Over 20% of cancer 'driver' genes encode chromatin regulators. Long noncoding RNAs (lincRNAs), which are dysregulated in various cancers, play a critical role in chromatin dynamics and gene regulation by interacting with key epigenetic regulators. It has been previously reported that the lincRNA HOTAIR mediates recruitment of polycomb repressive complex 2 (PRC2) leading to aberrant transcriptional silencing of tumor suppressor genes in glioma and breast cancer. Thus, lincRNA HOTAIR can serve as a promising therapeutic target. Herein, we identified a small-molecule compound AC1Q3QWB (AQB) as a selective and efficient disruptor of HOTAIR-EZH2 interaction, resulting in blocking of PRC2 recruitment and increasing tumor suppressors expression. Methods: Molecular docking and high-throughput screening were performed to identify the small compound, AQB. RIP and ChIRP assays were carried to assess the selective interference of AQB with the HOTAIR-EZH2 interaction. The effects of AQB on tumor malignancy were evaluated in a variety of cancer cell lines and orthotopic breast cancer models. The combination therapy of AQB and 3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2 was used in vitro and in orthotopic breast cancer and glioblastoma patient-derived xenograft (PDX) models. Results: Tumor cells highly expressing HOTAIR and EZH2 were sensitive to AQB. APC2, as one of the target genes, was significantly up-regulated by AQB and led to degradation of β-catenin resulting in suppression of Wnt/β-catenin signaling which may contribute to inhibition of tumor growth and metastasis in vitro and in orthotopic breast cancer models. Remarkably, AQB enhanced the toxicity of DZNep in vitro. In orthotopic breast cancer and glioblastoma patient-derived xenografts (PDX) models, the combination of low doses of AQB and DZNep realized much better killing than DZNep treatment alone. Conclusion: AQB is a HOTAIR-EZH2 inhibitor, which blocks PRC2 recruitment and has great potential as an effective agent for targeted cancer therapy.

Dataset Information

PRC2 is dispensable for HOTAIR-mediated transcriptional repression.

Publications

PRC2 is dispensable for <i>HOTAIR</i>-mediated transcriptional repression.

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