The hallmarks of cancer: a long non-coding RNA point of view

Abstract

With the advent of next generation sequencing methods and progress in transcriptome analysis, it became obvious that the human genome contains much more than just protein-coding genes. In fact, up to 70% of our genome is transcribed into RNA that does not serve as templates for proteins. In this review, we focus on the emerging roles of these long non-coding RNAs (lncRNAs) in the field of tumor biology. Long ncRNAs were found to be deregulated in several human cancers and show tissue-specific expression. Functional studies revealed a broad spectrum of mechanisms applied by lncRNAs such as HOTAIR, MALAT1, ANRIL or lincRNA-p21 to fulfill their functions. Here, we link the cellular processes influenced by long ncRNAs to the hallmarks of cancer and therefore provide an ncRNA point-of-view on tumor biology. This should stimulate new research directions and therapeutic options considering long ncRNAs as novel prognostic markers and therapeutic targets.

Figure 1. Cellular functions of long ncRNAs. LncRNAs can act in diverse ways in the cell. In general, they can regulate gene expression, influence protein localization (D) and are important for the formation of cellular substructures or protein complexes, where they fulfill scaffolding functions (C; H). Regulating gene expression is one of the best studied functions of lncRNA and multiple mechanisms are applied by lncRNAs. (A) LncRNAs coul be processed into small, single- or double-stranded RNAs that could act as endo-siRNAs targeting other RNAs, which subsequently leads to target degradation. (B) LncRNAs can act as “miRNA sponge” and sequester miRNAs to inactivate these small regulatory RNAs. This influences the expression of miRNA target genes. (D) The interaction of lncRNAs with proteins they can modulate protein activity and localization. For example, the lncRNA NRON (non-coding repressor of NFAT) binds to the cellular transcription factor NFAT (nuclear factor of activated T cells). This regulates nuclear-cytoplasmic trafficking of NFAT and finally leading to an repression of NFAT target gene expression. (E) Furthermore, lncRNA regulate gene transcription via recruiting transcription factors to their target gene promoters, therefore activating gene expression. However, they can also block binding of general transcription factors, potentially via formation of RNA-DNA-Triplexes. (F) LncRNAs contribute to transcriptome complexity, as they can regulate alternative splicing of pre-mRNAs. (G) The balance between transcriptional active euchromatin and silent heterochromatin is controlled by lncRNAs. They can interact with chromatin remodeling complexes and induce local or global changes in chromatin packaging.^,