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Open AccessJournal ArticleDOI

The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells

TLDR
A loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target.
Abstract
The long non-coding RNA MALAT1, also known as MALAT-1 or NEAT2, is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using Zinc Finger Nucleases. The achieved 1000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with antisense oligonucleotides provides a potential therapeutic approach to prevent lung cancer metastasis with MALAT1 serving as both, predictive marker and therapeutic target. Lastly, regulating gene expression, but not alternative splicing is the critical function of MALAT1 in lung cancer metastasis. In summary, ten years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis.

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RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.

TL;DR: An architectural role for RUNX1 in fine-tuning local interactions rather than in global organization is suggested, providing novel insight into RunX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNx1-dependent compromised gene expression in breast cancer cells.
Journal ArticleDOI

From biomarkers to therapeutic targets—the promises and perils of long non-coding RNAs in cancer

TL;DR: Prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets are highlighted and introduced.
Journal ArticleDOI

Knockdown of long non-coding RNA MALAT1 increases the blood–tumor barrier permeability by up-regulating miR-140

TL;DR: The fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas, is demonstrated.
Journal ArticleDOI

HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2.

TL;DR: The demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell and the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the Liver cancer stem cells.
References
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Journal ArticleDOI

The hallmarks of cancer.

TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
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Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis

TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Journal ArticleDOI

The Transcriptional Landscape of the Mammalian Genome

Piero Carninci, +197 more
- 02 Sep 2005 - 
TL;DR: Detailed polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
Journal ArticleDOI

Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes

TL;DR: The results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
Journal ArticleDOI

RNA Maps Reveal New RNA Classes and a Possible Function for Pervasive Transcription

TL;DR: Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes and support a highly interleaved organization of the human transcriptome.
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