The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy

Abstract

Long noncoding RNAs are recently emerging as critical factors of tumorigenesis. Originally regarded as a pre-messenger RNA (mRNA) splicing regulator, the long noncoding RNA MALAT1 has been demonstrated to regulate gene transcription by binding histone modification enzymes and transcription factors, and to regulate mRNA and protein expression post-transcriptionally by binding microRNAs (miRNAs) and acting as a sponge. Early studies consistently report that MALAT1 is up-regulated in human cancer tissues of various organ origins, particularly metastatic cancer tissues, that high levels of MALAT1 expression in cancer tissues are associated with poor patient prognosis, and that MALAT1 induces cancer cell proliferation, migration, and invasion in vitro and tumor metastasis in mice. By contrast, by analyzing multiple independent large datasets, MALAT1 have very recently been found to be down-regulated in human colorectal and breast cancer tissues, and low MALAT1 expression is associated with decreased patient survival. By binding to the transcription factor TEAD, MALAT1 suppresses metastasis gene expression, colorectal and breast cancer cell migration, invasion, and metastasis in vitro and in mice. MALAT1 has therefore been proposed to function as a tumor suppressor in colorectal and breast cancers. More comprehensive studies with multiple independent cohorts of human cancer tissues of various organ origins, in vitro and in vivo function, and mechanism studies with rescue experiments are required to confirm the oncogenic or tumor suppressive role of MALAT1 in other cancers.

Keywords: MALAT1; cell migration; gene expression; invasion; metastasis; pre-messenger RNA splicing; tumorigenesis.

Figure 1

Models of MALAT1-mediated oncogenic and tumor suppressive effects through transcriptional regulation of oncogenes and tumor suppressors. (A) MALAT1 forms a RNA-protein complex with the Polycomb Repressive Complex 2 (PRC2) component proteins SUZ12 and EZH2 at the promoters of tumor suppressor genes such as E-cadherin, N-Myc downregulated gene-1 (NDRG1), p21, and p27, leading to histone H3K27 trimethylation, transcription repression, epithelial mesenchymal transition (EMT), and tumorigenesis. (B) MALAT1 binds and sequesters transcription factor TEAD proteins and thereby blocks TEAD proteins from associating with their co-activator YAP and the promoters of oncogenes such as integrin β4 (ITGB4) and vascular endothelial growth factor (VEGF), leading to oncogene transcriptional suppression and tumor suppressive effects. (C) After Pc2 protein is demethylated by the histone H3K9 demethylase JMJD2C, MALAT1 binds unmethylated Pc2 protein to promote E2F1 SUMOylation, transcription activation of E2F1 target genes, and cell proliferation.