Long noncoding 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.

Retracted: Long noncoding RNA MALAT1 promotes the stemness of esophageal squamous cell carcinoma by enhancing YAP transcriptional activity

“…LncRNA MALAT1 has been revealed to promoter cancer progression in different cancers. However, MALAT1 has been shown to suppress breast cancer metastasis in a MALAT1-knockout mice model [11]. MALAT1 potentiated the epithelial-mesenchymal transition and angiogenesis by regulating miR-126-5p activity in colorectal cancer [10].…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…Apart from defects in endothelial cell proliferation and retinal vascularization, Malat1 ‐deficient mice do not show any overt developmental abnormalities or an overall reduction in viability . Interestingly, a recent study shed new light upon the molecular function of MALAT1 and its role in cancer metastasis . Through a series of genetic and biochemical experiments, it was demonstrated that MALAT1 acts as a suppressor of metastasis in different mouse models of breast cancer and that this effect is a result of the direct binding and inactivation of the pro‐metastatic transcription factor TEAD.…”

“…58,60,61 Interestingly, a recent study shed new light upon the molecular function of MALAT1 and its role in cancer metastasis. 62 Through a series of genetic and biochemical experiments, it was demonstrated that MALAT1 acts as a suppressor of metastasis in different mouse models of breast cancer and that this effect is a result of the direct binding and inactivation of the pro-metastatic transcription factor TEAD. These unexpected findings are in conflict with the previous literature on the oncogenic role of MALAT1 in human cancers and mouse tumor models, which suggested a metastasis-promoting function for this lncRNA.…”

Commentary on: The potency of lncRNA MALAT1/miR-155 in altering asthmatic Th1/Th2 balance by modulation of CTLA4

“…As indicated by its name, MALAT1 has been associated with poor clinical outcomes in lung cancer [31]. However, gene inactivation studies in mice yielded conflicting results with studies showing both enhanced [35] and decreased [36] metastatic potential. Besides regulating miRNA, MALAT1 directs the polycomb repressor complex (PRC) to methylate and silence key genes [37].…”

“…Besides regulating miRNA, MALAT1 directs the polycomb repressor complex (PRC) to methylate and silence key genes [37]. MALAT1 also influences gene expression by binding and inactivating the Tead family of transcription factors [35]. Through its varied effects, MALAT1 regulates PI3K-AKT, MAPK, WNT and NF-κB signaling pathways [38], which influence critical biological processes like proliferation, inflammation, cell survival and metabolic function.…”