How miRs and mRNA deadenylases could post-transcriptionally regulate expression of tumor-promoting protein PLD

Abstract Phospholipase D (PLD) plays a key role in both cell membrane lipid reorganization and architecture, as well as a cell signaling protein via the product of its enzymatic reaction, phosphatidic acid (PA). PLD is involved in promoting breast cancer cell growth, proliferation, and metastasis and both gene and protein expression are upregulated in breast carcinoma human samples. In spite of all this, the ultimate reason as to why PLD expression is high in cancer cells vs. their normal counterparts remains largely unknown. Until we understand this and the associated signaling pathways, it will be difficult to establish PLD as a bona fide target to explore new potential cancer therapeutic approaches. Recently, our lab has identified several molecular mechanisms by which PLD expression is high in breast cancer cells and they all involve post-transcriptional control of its mRNA. First, PA, a mitogen, functions as a protein and mRNA stabilizer that counteracts natural decay and degradation. Second, there is a repertoire of microRNAs (miRs) that keep PLD mRNA translation at low levels in normal cells, but their effects change with starvation and during endothelial-to-mesenchymal transition (EMT) in cancer cells. Third, there is a novel way of post-transcriptional regulation of PLD involving 3′-exonucleases, specifically the deadenylase, Poly(A)-specific Ribonuclease (PARN), which tags mRNA for mRNA for degradation. This would enable PLD accumulation and ultimately breast cancer cell growth. We review in depth the emerging field of post-transcriptional regulation of PLD, which is only recently beginning to be understood. Since, surprisingly, so little is known about post-transcriptional regulation of PLD and related phospholipases (PLC or PLA), this new knowledge could help our understanding of how post-transcriptional deregulation of a lipid enzyme expression impacts tumor growth.