Pseudogenes in Human Cancer

Abstract

Recent advances in the analysis of RNA sequencing data have shown that pseudogenes are highly specific markers of cell identity and can be used as diagnostic and prognostic markers. Furthermore, genetically engineered mouse models have recently provided compelling support for a causal link between altered pseudogene expression and cancer. In this review, we discuss the most recent milestones reached in the pseudogene field and the use of pseudogenes as cancer classifiers.

Keywords: animal models of cancer; cancer; ceRNAs; diagnostic markers; mutagenic factors; prognostic markers; pseudogenes.

Figure 1

An overview of pseudogene functions. (A–E) Parental gene-related functions of pseudogenes (left). (A) Pseudogenes and parental genes can exchange genomic DNA through gene conversion or homologous recombination. The pseudogene promoter can also affect the transcription of the parental gene. (B) Pseudogene RNA transcribed in sense and antisense orientation can affect the transcription of the parental gene at the epigenetic level. (C) Pseudogene sense and antisense transcripts can form a double-stranded RNA that is cleaved into endogenous siRNAs. In turn, esiRNAs affect the parental gene expression at the post-transcriptional level. (D) Pseudogene RNA transcribed in sense orientation can compete with parental mRNA for the binding of microRNAs, RNA-binding proteins (RBPs), or the translational machinery. (E) Pseudogene proteins can be highly homologous to parental proteins, but be expressed in a different context (tissue, cellular compartment, pathophysiological condition). They can also carry gain-of-function mutations. Finally, they may affect the function of the parental proteins even if they are not fully functional. (F–H) Parental gene-unrelated functions of pseudogenes (center). (F) The de novo acquisition of new exons at either side (processed pseudogenes) or in the middle (non-processed pseudogenes) of their genomic sequence contributes to distinguishing the sequence, and hence the function, of pseudogenes compared to that of their parental genes. (G) Pseudogene RNA transcribed in antisense orientation can affect the stability of the sense pseudogenic transcript. (H) Pseudogene RNAs can be matured into microRNAs or translated into antigenic peptides. (I–K) Parental gene-unrelated functions of pseudogenes (right). (I) The “landing” of a processed pseudogene within other genes can produce several different scenarios. If the insertion site is an upstream intron, then the processed pseudogene will be cotranscribed with its host gene as a non-coding fusion transcript. If a protein is eventually translated, then it will most likely be short and contain only the pseudogene sequence. Pseudogenes inserted in upstream introns can also affect the transcription of the host gene by epigenetic silencing. If the insertion site is a more downstream intron, then the processed pseudogene will be cotranscribed with its host gene as a coding fusion transcript and the translated protein will be a chimera that is composed of both the gene and the pseudogene sequence. If the insertion site is in a 3′-UTR-expressing exon, then the fusion transcript will display an altered post-transcriptional regulation. If the pseudogene lands in a coding exon, the result will be insertional mutagenesis that will likely abrogate the expression of the host gene. (J) Pseudogenes and adjacent genes can be transcribed into joint read-through transcripts and translated into chimerical proteins. (K) Pseudogene RNAs working as source of esiRNAs or as sponges can also affect other unrelated genes besides the parental genes. The DNA/RNA/protein of a representative pseudogene, parental gene, and unrelated gene are shown in red, blue, and green, respectively. For a detailed overview of parental gene-related and unrelated functions of pseudogenes, please refer to Ref. (7) with updates reported in Ref. (–18). For a list of the pseudogenes that function as sponges for microRNAs (a.k.a. competing endogenous RNAs) in cancer, please refer to Table 1.