Long noncoding RNA MALAT1 suppresses breast cancer metastasis

Jongchan Kim, Hai Long Piao, Beom Jun Kim, Fan Yao, Zhenbo Han, Yumeng Wang, Zhenna Xiao, Ashley N. Siverly, Sarah E. Lawhon, Baochau N. Ton, Hyemin Lee, Zhicheng Zhou, Boyi Gan, Shinichi Nakagawa, Matthew J. Ellis, Han Liang, Mien Chie Hung, M. James You, Yutong Sun, Li Ma

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1705-1715
Number of pages11
JournalNature Genetics
Volume50
Issue number12
DOIs
StatePublished - Dec 1 2018

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Long Noncoding RNA
Breast Neoplasms
Neoplasm Metastasis
Gene Silencing
Heterografts
Transgenic Mice
Genes
Transcription Factors
Phenotype
Lung

ASJC Scopus subject areas

  • Genetics

Cite this

Kim, J., Piao, H. L., Kim, B. J., Yao, F., Han, Z., Wang, Y., ... Ma, L. (2018). Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nature Genetics, 50(12), 1705-1715. https://doi.org/10.1038/s41588-018-0252-3

Long noncoding RNA MALAT1 suppresses breast cancer metastasis. / Kim, Jongchan; Piao, Hai Long; Kim, Beom Jun; Yao, Fan; Han, Zhenbo; Wang, Yumeng; Xiao, Zhenna; Siverly, Ashley N.; Lawhon, Sarah E.; Ton, Baochau N.; Lee, Hyemin; Zhou, Zhicheng; Gan, Boyi; Nakagawa, Shinichi; Ellis, Matthew J.; Liang, Han; Hung, Mien Chie; You, M. James; Sun, Yutong; Ma, Li.

In: Nature Genetics, Vol. 50, No. 12, 01.12.2018, p. 1705-1715.

Research output: Contribution to journalArticle

Kim, J, Piao, HL, Kim, BJ, Yao, F, Han, Z, Wang, Y, Xiao, Z, Siverly, AN, Lawhon, SE, Ton, BN, Lee, H, Zhou, Z, Gan, B, Nakagawa, S, Ellis, MJ, Liang, H, Hung, MC, You, MJ, Sun, Y & Ma, L 2018, 'Long noncoding RNA MALAT1 suppresses breast cancer metastasis', Nature Genetics, vol. 50, no. 12, pp. 1705-1715. https://doi.org/10.1038/s41588-018-0252-3
Kim J, Piao HL, Kim BJ, Yao F, Han Z, Wang Y et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nature Genetics. 2018 Dec 1;50(12):1705-1715. https://doi.org/10.1038/s41588-018-0252-3
Kim, Jongchan ; Piao, Hai Long ; Kim, Beom Jun ; Yao, Fan ; Han, Zhenbo ; Wang, Yumeng ; Xiao, Zhenna ; Siverly, Ashley N. ; Lawhon, Sarah E. ; Ton, Baochau N. ; Lee, Hyemin ; Zhou, Zhicheng ; Gan, Boyi ; Nakagawa, Shinichi ; Ellis, Matthew J. ; Liang, Han ; Hung, Mien Chie ; You, M. James ; Sun, Yutong ; Ma, Li. / Long noncoding RNA MALAT1 suppresses breast cancer metastasis. In: Nature Genetics. 2018 ; Vol. 50, No. 12. pp. 1705-1715.
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N2 - 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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