The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma 
transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant 
transcript 2), is a highly conserved nuclear noncoding RNA (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 1,000-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 (ASO) blocking MALAT1 prevent metastasis formation after tumor 
implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic 
approach to prevent lung cancer metastasis with this ncRNA serving as both 
predictive marker and therapeutic target. Finally, regulating gene expression, 
but not alternative splicing, is the critical function of MALAT1 in lung cancer 
metastasis. In summary, 10 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.