Journal
MOLECULAR ONCOLOGY
Volume 10, Issue 5, Pages 663-676Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2015.12.006
Keywords
Mammalian cells; Gene expression; Cell signaling; Breast cancer; RNA role
Categories
Funding
- National Institutes of Health (NIH) [HL056653-14]
- American Heart Association [13GRNT17230097]
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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 Shail. 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. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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