The long non-coding RNA MALAT1 is an essential gene regulator for lung cancer metastasis in a novel human knockout model

Gutschner, T., Hammerle, M., Eissmann, M., Hsu, J., Kim, Y., Hung, G. N., Revenko, A., Arun, G., Stentrup, M., Gross, M., Zornig, M., MacLeod, A. R., Spector, D. L., Diederichs, S. (2013) The long non-coding RNA MALAT1 is an essential gene regulator for lung cancer metastasis in a novel human knockout model. Cancer Research, 73 (8 (Sup). p. 1121. ISSN 0008-5472

URL: http://cancerres.aacrjournals.org/cgi/content/shor...
DOI: 10.1158/1538-7445.am2013-1121

Abstract

The long non-coding RNA MALAT1 was one of the first lncRNAs associated with cancer: it is a highly conserved nuclear ncRNA and a predictive marker for metastasis development in lung cancer. However, its high abundance and nuclear localization have greatly hampered its functional analysis since it is only inefficiently knocked down by RNA interference (RNAi). To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements site-specifically into the MALAT1 locus using Zinc Finger Nucleases (ZFN).This approach yielded a more than 1000-fold silencing of MALAT1 providing a unique loss-of-function model. Proposed mechanisms of action of MALAT1 include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression inducing a signature of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft model. Encouraged by this discovery of the essential function of MALAT1 in lung cancer metastasis, we wanted to analyze whether MALAT1 could also be therapeutically targeted: We developed Antisense oligonucleotides (ASOs) effectively blocking MALAT1 expression in the cell culture and in the animal. Notably, MALAT1-ASO treatment prevents 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.

Item Type: Paper
Additional Information: Meeting Abstract
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
diseases & disorders > cancer > cancer types > lung cancer
diseases & disorders > cancer > metastasis
CSHL Authors:
Communities: CSHL labs > Spector lab
Depositing User: Matt Covey
Date Deposited: 11 Apr 2014 15:56
Last Modified: 26 Jan 2015 15:10
URI: http://repository.cshl.edu/id/eprint/29756

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