The transcription factors Slug (SNAI2) and Snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion

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Slug (SNAI2) and Snail (SNAI1) are master regulatory transcription factors for organogenesis and wound healing, and they are involved in the epithelial to mesenchymal transition (EMT) of cancer cells. We found that the activity of phospholipase D isoform 2 (PLD2) is highly increased in cancers with larger size and poor prognosis (MDA-MB-231 versus MCF-7 cells), so we determined if Snail or Slug were responsible for PLD2 gene transcription regulation. Unexpectedly, we found that PLD2 expression was positively regulated by Slug but negatively regulated by Snail. The differential effects are amplified in breast cancer cells over normal cells and with MDA-MB-231 more robustly than MCF-7. Slug putatively binds to the PLD2 promoter and transactivates it, which is negated when Slug and Snail compete with each other. Meanwhile, PLD2 has a negative effect on Snail expression and a positive effect on Slug, thus closing a feedback loop between the lipase and the transcription factors. Further, PA, the product of PLD2 enzymatic reaction, has profound effects on its own and it further regulates the transcription factors. Thus, we show for the first time that the overexpressed PLD2 in human breast tumors is regulated by Slug and Snail transcription factors. The newly uncovered feedback loops in highly invasive cancer cells have important implications in the process of EMT.Graphical abstractHighlightsThe transcription factors Slug and Snail play a key role in the physiological processes of organogenesis and wound healing.They are also “used” by cells in pathological conditions such as cancer, for the process of metastasis.We report that Slug and Snail affect breast cancer cell invasion by regulating the signaling protein PLD and the mitogen PA.Slug is a positive regulator of PLD, whereas Snail is a repressor in to PLD-driven cell invasion of breast cancer cells.A novel negative feedback between Slug and Snail is differentially regulated in highly and low invasive cancer cells.

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