Long Noncoding RNA and Epithelial Mesenchymal Transition in Cancer

Abstract

Epithelial-mesenchymal transition (EMT) is a multistep process that allows epithelial cells to acquire mesenchymal properties. Fundamental in the early stages of embryonic development, this process is aberrantly activated in aggressive cancerous cells to gain motility and invasion capacity, thus promoting metastatic phenotypes. For this reason, EMT is a central topic in cancer research and its regulation by a plethora of mechanisms has been reported. Recently, genomic sequencing and functional genomic studies deepened our knowledge on the fundamental regulatory role of noncoding DNA. A large part of the genome is transcribed in an impressive number of noncoding RNAs. Among these, long noncoding RNAs (lncRNAs) have been reported to control several biological processes affecting gene expression at multiple levels from transcription to protein localization and stability. Up to now, more than 8000 lncRNAs were discovered as selectively expressed in cancer cells. Their elevated number and high expression specificity candidate these molecules as a valuable source of biomarkers and potential therapeutic targets. Rising evidence currently highlights a relevant function of lncRNAs on EMT regulation defining a new layer of involvement of these molecules in cancer biology. In this review we aim to summarize the findings on the role of lncRNAs on EMT regulation and to discuss their prospective potential value as biomarkers and therapeutic targets in cancer.

Keywords: Epithelial to Mesenchymal Transition (EMT); cancer; long noncoding RNAs (lncRNAs).

Figure 1

Schematic representation of different molecular mechanisms through which lncRNAs regulate EMT in cancer. (A) Examples of lncRNAs in epigenetic regulation. HOTTIP binds WDR5, part of the MLL complex, on the HOXA genes locus to promote H3K4me3 modification enhancing transcription. MALAT1 interacts with EZH2, part of the inhibiting complex PRC2, on E-CAD promoter. Subsequent tri-methylation of H3K27 impedes E-CAD transcription. HOTAIR can bind both LSD1 and PRC2 complexes on E-CAD promoter to transcriptionally silence it. Their binding provokes the displacement of CBP acetyl-transferase, switching H3K27 acetylation to methylation, and the de-methylation of H3K4. (B) Examples of lncRNAs in protein scaffolding. In the cytoplasm, linc00941 helps ANXA2 and GSKβ interaction which leads to β-Catenin phosphorylation inhibition, promoting its nuclear localization and the expression of its target genes. In a similar way, in the nucleus, NEAT1 functions as a scaffold for FOXN3 and SIN3A to inhibit GATA3 transcription. (C) Examples of lncRNAs in nuclear structures. NEAT1 and MALAT1 participate to maintain nuclear sub-structures, paraspeckles and speckles respectively, also contributing to their function. (D) Examples of lncRNAs and transcript processing. ZEB2-AS1 is an antisense lncRNA overlapping the 5’UTR of the ZEB2 gene. Its sequence is complementary to a splicing site of an intron containing an IRES region. ZEB2-AS1-mediated splicing skipping preserves the IRES element, directly enhancing ZEB2 translation. H19 lncRNAs is itself a reservoir of another ncRNA, miR-675, which, once processed, potentiate its pro-EMT role. Indeed, while H19 epigenetically impede E-CAD transcription, miR-675 positively regulates AKT/mTOR axis. (E) Examples of lncRNAs as ceRNAs. HOTTIP and linc00941 participate to SNAIL upregulation sponging miR-30b and miR-34a, respectively. MALAT1, whose transcription is enhanced by STAT3, promotes EMT by sponging miR-30a and miR-1, thus upregulating VIMENTIN and SLUG levels.