A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

Abstract

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.

PTTG3P promotes gastric tumour cell proliferation and invasion and is an indicator of poor prognosis

“…Poliseno and colleagues revealed that the PTENP1 3′UTR significantly suppressed cell proliferation in PTEN‐null PC3 cells, supporting the notion that PTENP1 could exert a tumour‐suppressive role independent of the parent PTEN gene 2. Likewise, ψPPM1K, a partial retrotranscript pseudogene containing inverted repeats capable of being processed into two endo‐siRNAs, regulates cell growth‐related target genes and exerts tumour‐suppressive activity independent of its cognate gene PPM1K 3.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…[176][177][178] Although PTEN promoter methylation has been reported, 179 an unknown but probably high proportion of these findings relate to cross-reactions with the pseudogene PTENP1. 180 Studying prostatic cancer, Pandolfi and co-workers 181,182 have shown PTENP1 to be transcribed and have provided evidence indicating it may act as a decoy, competing with the PTEN transcript for miRNA binding. If these findings are confirmed in other cancer forms as well, it may have significant implications to our understanding of PTEN regulation, but probably regulation of other genes as well.…”

Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

“…The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is involved in CoGAM The tumor suppressor PTEN, a major inhibitory regulator of the PI3K/AKT proliferation signaling pathway (Carracedo and Pandolfi, 2008), is also a shared target of miR-19 (Lewis et al, 2003) and miR-20 (Poliseno et al, 2010). In addition, in MDA-MB-231 cells, the PTEN protein was actually significantly increased by Drosha knockdown (Figure 5a), a result that was confirmed at the mRNA level ( Supplementary Figure 8).…”