The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Tony Gutschner,Monika Hämmerle,Moritz Eißmann,Jeff Hsu,Youngsoo Kim,Gene Hung,Alexey S. Revenko,Gayatri Arun,Marion Stentrup,Matthias Groß,Martin Zörnig,A. Robert MacLeod,David L. Spector,Sven Diederichs +13 more
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.read more
Citations
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References
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3′ End Processing of a Long Nuclear-Retained Noncoding RNA Yields a tRNA-like Cytoplasmic RNA
TL;DR: These findings reveal a 3' end processing mechanism by which a single gene locus can yield both a stable nuclear-retained noncoding RNA with a short poly(A) tail-like moiety and a small tRNA-like cytoplasmic RNA.
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ncRNA- and Pc2 Methylation-Dependent Gene Relocation between Nuclear Structures Mediates Gene Activation Programs
Liuqing Yang,Chunru Lin,Wen Liu,Jie Zhang,Kenneth A. Ohgi,Jonathan D. Grinstein,Pieter C. Dorrestein,Michael G. Rosenfeld +7 more
TL;DR: Observations delineate a molecular pathway linking the actions of subnuclear structure-specific ncRNAs and nonhistone protein methylation to relocation of transcription units in the three-dimensional space of the nucleus, thus achieving coordinated gene expression programs.
Journal ArticleDOI
The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult.
Bin Zhang,Gayatri Arun,Yuntao S. Mao,Zsolt Lazar,Gene Hung,Gourab Bhattacharjee,Xiaokun Xiao,Carmen J. Booth,Jie Wu,Jie Wu,Chaolin Zhang,David L. Spector +11 more
TL;DR: A Malat1 loss-of-function genetic model is characterized that indicates that Malat 1 is not essential for mouse pre- and postnatal development, and depletion of Mal at1 does not affect global gene expression, splicing factor level and phosphorylation status, or alternative pre-mRNA splicing.
Journal ArticleDOI
The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth.
Lars Henning Schmidt,Tilmann Spieker,Steffen Koschmieder,J Humberg,Dominik Jungen,Etmar Bulk,Antje Hascher,Danielle Wittmer,Alessandro Marra,Ludger Hillejan,Karsten Wiebe,Wolfgang E. Berdel,Rainer Wiewrodt,Carsten Müller-Tidow +13 more
TL;DR: In situ hybridization on paraffin-embedded lung cancer tissue probes revealed that high MALAT-1 RNA expression in squamous cell carcinoma of the lung was associated with a poor prognosis, and data indicate that MALat-1 expression levels are associated with patient survival and identify tumor-promoting functions of MALatin 1.
Journal ArticleDOI
MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes
Keiko Tano,Rie Mizuno,Tomoko Okada,Randeep Rakwal,Randeep Rakwal,Junko Shibato,Yoshinori Masuo,Kenichi Ijiri,Nobuyoshi Akimitsu +8 more
TL;DR: It is suggested that MALAT‐1 is a novel class of non‐coding RNA that promotes cell motility through transcriptional and post‐transcriptional regulation of motility related gene expression.
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