title: The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells.
abstract: 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.
authors.affiliation: Helmholtz-University-Group Molecular RNA Biology & Cancer, German Cancer Research Center DKFZ & Institute of Pathology, Heidelberg, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Gutschner
authors.forename: Monika
authors.initials: M
authors.lastname: Hämmerle
authors.forename: Moritz
authors.initials: M
authors.lastname: Eissmann
authors.forename: Jeff
authors.initials: J
authors.lastname: Hsu
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Alexey
authors.initials: A
authors.lastname: Revenko
authors.forename: Gayatri
authors.initials: G
authors.lastname: Arun
authors.forename: Marion
authors.initials: M
authors.lastname: Stentrup
authors.forename: Matthias
authors.initials: M
authors.lastname: Gross
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.forename: David L
authors.initials: DL
authors.lastname: Spector
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005786:Gene Expression Regulation; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C557041:MALAT1 long non-coding RNA, human; D016376:Oligonucleotides, Antisense; D062085:RNA, Long Noncoding