Non-coding RNAs in cancers with chromosomal rearrangements: the signatures, causes, functions and implications

Abstract

Chromosomal translocation leads to the juxtaposition of two otherwise separate DNA loci, which could result in gene fusion. These rearrangements at the DNA level are catastrophic events and often have causal roles in tumorigenesis. The oncogenic DNA messages are transferred to RNA molecules, which are in most cases translated into cancerous fusion proteins. Gene expression programs and signaling pathways are altered in these cytogenetically abnormal contexts. Notably, non-coding RNAs have attracted increasing attention and are believed to be tightly associated with chromosome-rearranged cancers. These RNAs not only function as modulators in downstream pathways but also directly affect chromosomal translocation or the associated products. This review summarizes recent research advances on the relationship between non-coding RNAs and chromosomal translocations and on diverse functions of non-coding RNAs in cancers with chromosomal rearrangements.

Keywords: chromosomal translocation; fusion protein; gene regulation; non-coding RNA; non-coding fusion transcript.

Figure 1

The causes of the dysregulation of ncRNAs. (A) Fusion proteins with transcriptional activity alter the expressions of ncRNAs by directly binding to their regulatory elements and recruiting epigenetic modification enzymes. (B and C) The dysregulation of ncRNAs is mediated by the downstream effectors of fusion proteins with transcriptional activity or kinase activity. (D) The dysregulation of ncRNAs is due to the disturbance of RNA processing/formation process by fusion proteins. (E) The loss or amplification of ncRNAs as concomitant mutations. (F) The activation or silencing of ncRNA expressions is directly triggered by chromosomal translocation.

Figure 2

The various modes of actions of ncRNAs in fusion protein-driven cancers. (A) The miRNAs function in a teeterboard manner. (B–E) The lncRNAs play their roles by regulating translation (B), competing for miRNA binding (C), recruiting chromatin-remodeling complex (D), and binding proteins to regulate gene expressions (E). (F and G) The lncRNAs possibly facilitate AID-dependent gene translocation by transcription opposite to the sense strands (F) or bring two translocation partners into close proximity by directing interacting with their DNA loci (G). (H) Fusion proteins deregulate snoRNA and/or rRNA to exert procancer functions. (I–K) The ncRNAs can directly target fusion transcripts (I), regulate fusion protein degradation (J), or the nucleoplasmic transport of fusion mRNA pathways (K).

Figure 3

ncRNAs are directly involved in chromosome translocation. (A) ncRNA-convergent fusions. (B) The chromosomal translocation sites reside in the ncRNA regions: production of new ncRNAs by juxtaposition of regulatory elements upstream of non-coding regions or disruption of original ncRNA. (C) The fusions of non-coding regions with coding regions lead to the dysregulations of coding products and subsequent alterations of related signaling pathways. (D) The coding fusion transcripts or the derived non-coding isoforms, such as circRNAs by back-splicing, function as regulatory RNAs.