MALAT1 has previously been described as a metastasis-promoting long noncoding RNA (lncRNA). We show here, however, that targeted inactivation of the Malat1 gene in a transgenic mouse model of breast cancer, without altering the expression of its adjacent genes, promotes lung metastasis, and that this phenotype can be reversed by genetic add-back of Malat1. Similarly, knockout of MALAT1 in human breast cancer cells induces their metastatic ability, which is reversed by re-expression of Malat1. Conversely, overexpression of Malat1 suppresses breast cancer metastasis in transgenic, xenograft, and syngeneic models. Mechanistically, the MALAT1 lncRNA binds and inactivates the prometastatic transcription factor TEAD, preventing TEAD from associating with its co-activator YAP and target gene promoters. Moreover, MALAT1 levels inversely correlate with breast cancer progression and metastatic ability. These findings demonstrate that MALAT1 is a metastasis-suppressing lncRNA rather than a metastasis promoter in breast cancer, calling for rectification of the model for this highly abundant and conserved lncRNA.
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The data that support the findings of this study are available from the corresponding author upon reasonable request. The RNA-seq data have been deposited at the Gene Expression Omnibus under accession number GSE110239.
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We thank W. Muller for providing MMTV-PyMT mice (C57BL/6 background), X. Zhang for providing luciferase-expressing LM2 cells, and J. Jacobson and L. Xin for providing ITGB4–luciferase and FU-luciferase-CRW/RFP constructs, respectively. We thank J. Zhang and MD Anderson’s shRNA and ORFeome Core, Small Animal Imaging Facility, Flow Cytometry and Cellular Imaging Core Facility, Sequencing and Microarray Facility, and Characterized Cell Line Core Facility for technical assistance. We thank all members of the Ma laboratory for discussions; J. Chen for critical reading of the manuscript; and J.-H. Yoon and M. Gorospe for advice on the CLIP assay. L.M. is supported by US National Institutes of Health (NIH) grants R01CA166051 and R01CA181029; a Cancer Prevention and Research Institute of Texas (CPRIT) grant (RP150319); and a Stand Up To Cancer Innovative Research Grant (403235). M.J.Y. was supported in part by NIH grants R01CA164346 and R01CA200703, and CPRIT RP140402. M.-C.H. is supported by National Breast Cancer Foundation Inc. and The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund. H. Liang is supported by NIH grants R01CA175486 and U24CA209851. M.J.E is supported by CPRIT grant RR140033. B.G. is supported by NIH grants R01CA181196 and R01CA190370.
The authors declare no competing interests.
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Supplementary Figures 1–10, Supplementary Tables 1–3 and Supplementary Note
Time-lapse video microscopy of control MDA-MB-231 cells
Time-lapse video microscopy of MALAT1-knockout MDA-MB-231 cells
Time-lapse video microscopy of MALAT1-knockout MDA-MB-231 cells with ectopic expression of mouse Malat1
Time-lapse video microscopy of control LM2 cells
Time-lapse video microscopy of Malat1-overexpressing LM2 cells
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Kim, J., Piao, HL., Kim, BJ. et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet 50, 1705–1715 (2018). https://doi.org/10.1038/s41588-018-0252-3
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