title: The transcription factors Slug (SNAI2) and Snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion.
abstract: 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.
authors.affiliation: Wright State University Boonshoft School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, OH 45435, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Ganesan
authors.affiliation: Wright State University Boonshoft School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, OH 45435, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mallets
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women Hospital and Harvard Medical School, Boston, MA 02115, USA; Wright State University Boonshoft School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, OH 45435, USA. Electronic address: julian.cambronero@wright.edu.
authors.forename: Julian
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D010739:Phospholipase D / Q000235:genetics*; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; C105606:phospholipase D2; D010739:Phospholipase D
keywords: Breast cancer; Cell signaling; Gene expression; Mammalian cells; RNA role