RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

Abstract

The majority of the genome is transcribed into pieces of non-(protein) coding RNA, among which long non-coding RNAs (lncRNAs) constitute a large group of particularly versatile molecules that govern basic cellular processes including transcription, splicing, RNA stability, and translation. The frequent deregulation of numerous lncRNAs in cancer is known to contribute to virtually all hallmarks of cancer. An important regulatory mechanism of lncRNAs is the post-transcriptional regulation mediated by RNA-binding proteins (RBPs). So far, however, only a small number of known cancer-associated lncRNAs have been found to be regulated by the interaction with RBPs like human antigen R (HuR), ARE/poly(U)-binding/degradation factor 1 (AUF1), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and tristetraprolin (TTP). These RBPs regulate, by various means, two aspects in particular, namely the stability and the localization of lncRNAs. Importantly, these RBPs themselves are commonly deregulated in cancer and might thus play a major role in the deregulation of cancer-related lncRNAs. There are, however, still many open questions, for example regarding the context specificity of these regulatory mechanisms that, in part, is based on the synergistic or competitive interaction between different RBPs. There is also a lack of knowledge on how RBPs facilitate the transport of lncRNAs between different cellular compartments. Compared to protein-coding genes, lncRNAs are poorly conserved between different species and their expression levels are rather low [7,8]. Initially, this led to the belief that they were nothing but transcriptional noise [6][7][8]. Soon, however, it was discovered that lncRNAs do exhibit considerable functionality, for example as regulators of transcription [6][7][8]. Mechanisms of transcriptional regulation by lncRNAs are multifarious and can occur either in cis or in trans, meaning either closer to or further away from the lncRNA's site of transcription, respectively [6,7]. A frequent mechanism of transcriptional regulation via lncRNAs is the recruitment, or prevention of such, of components of chromatin or histone-modifying complexes, like polycomb repressive complexes or histone deacetylase complexes [11][12][13]. LncRNAs can also direct transcription factors or cofactors to promoter regions of genes and facilitate the formation of chromatin loops between distant enhancers and promoters, as observed for some eRNAs [9,[14][15][16][17]. Another way that they can impact transcription is by interfering with the RNA polymerase II transcription machinery, thereby blocking transcriptional initiation or elongation [18]. LncRNAs are important regulators not only at the level of transcription but also at the post-transcriptional level [6,7]. They regulate pre-mRNA splicing by interacting with splicing factors or with the mRNA itself [19][20][21][22]. A well-studied example for this is metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNA that interacts with serine/arginine (SR) spl...

Comprehensive analysis of the functions and prognostic significance of RNA-binding proteins in bladder urothelial carcinoma

“…RBPs and RNAs assemble into a dynamic complex, called ribonucleoprotein (RNP), which regulates almost every stage of RNA lifecycle [29]. An important regulatory mechanism of lncRNAs is RNA-binding protein-mediated post-transcriptional regulation [30]. This post-transcriptional regulation is a vital approach of coding and non-coding RNAs, and is mainly promoted by RNA-binding proteins, since they dynamically coordinate the maturation, transport, and stability of all RNA types [9].…”

RNA-Binding Proteins in Cancer: Functional and Therapeutic Perspectives

“…The subcellular localization of an mRNA or lncRNA is an important factor in the regulation of its stability and translation, and cancer-related RBPs often bind to RNAs to coordinate where they are localized and translated [ 75 , 76 ].…”

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

“…For example, association of proteins with lncRNAs can affect the localization and stability of both, the non-coding transcript as well as the protein. These interactions are of functional relevance for diverse cellular processes including, but not limited to transcriptional and epigenetic gene expression control, splicing, DNA damage signaling, tissue homeostasis and differentiation as well as cancer cell invasion and metastasis [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. Furthermore, recent studies have identified several RBPs that regulate the processing and biogenesis of miRNAs and their precursors [ 78 , 79 ].…”