Phosphatidic Acid (PA) can Displace PPARα/LXRα Binding to The EGFR Promoter Causing its Transrepression in Luminal Cancer Cells.
The expression of the epidermal growth factor receptor (EGFR) is highly regulated in normal cells, whereas some cancer cells have high constitutive levels. Understanding naturally-occurring ways of downregulating EGFR in cancer cells was investigated. Phosphatidic acid (PA) or Nuclear Receptors (NR) PPARα/RXRα/LXRα, enhance EGFR expression, mediated by the promoter region -856(A) to -226(T). Unexpectedly, the combination of NRs and PA caused repression. PA induces a conformational change in the nuclear receptor PPARα (increase of alpha-helices at the expense of decreasing beta-sheets), as evidenced by circular dichroism. This represses the naturally-enhancing capability of PPARα on EGFR transcription. PPARα-overexpressing cells in the presence of PA > 300 nM or the enzyme that produces it, phospholipase D (PLD), downregulate EGFR expression. The reasons are two-fold. First, PA displaces PPARα binding to the EGFR promoter at those concentrations. Second, NR heterodimer-dependent promoter activity is weakened in the presence of PA in vivo. Since other genes considered (β-catenin, cyclin D3, PLD2 and ACOX-1) are also downregulated with a PA + PPARα combination, the transrepression appears to be a global phenomenon. Lastly, the reported effect is greater in MCF-7 than in MDA-MB-231 breast cancer cells, which could provide a novel basis for regulating excessive expression of EGFR in luminal cancer cells.
Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, Ohio 45435, USA.
Madhu
M
Mahankali
Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, Ohio 45435, USA.
Terry
T
Farkaly
Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, Ohio 45435, USA.
Shimpi
S
Bedi
Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, Ohio 45435, USA.
Heather A
HA
Hostetler
Wright State University School of Medicine, Department of Biochemistry and Molecular Biology, Dayton, Ohio 45435, USA.
Julian
J
Gomez-Cambronero
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D000071518:Liver X Receptors; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000494:pharmacology*; D011401:Promoter Regions, Genetic
D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D010712:Phosphatidic Acids; D004247:DNA; D066246:ErbB Receptors