Long non-coding RNA MALAT1 suppresses breast cancer metastasis

Abstract

MALAT1 has previously been described as a metastasis-promoting long non-coding RNA (lncRNA). Unexpectedly, we found that targeted inactivation of the Malat1 gene without altering the expression of its adjacent genes in a transgenic mouse model of breast cancer promoted lung metastasis, and importantly, this phenotype was reversed by genetic add-back of Malat1. Similarly, knockout of MALAT1 in human breast cancer cells induced their metastatic ability, which was reversed by Malat1 re-expression. Conversely, overexpression of Malat1 suppressed breast cancer metastasis in transgenic, xenograft, and syngeneic models. Mechanistically, MALAT1 binds and inactivates the pro-metastatic transcription factor TEAD, blocking 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 a highly abundant and conserved lncRNA.