p63 promotes cell survival through fatty acid synthase.
There is increasing evidence that p63, and specifically DeltaNp63, plays a central role in both development and tumorigenesis by promoting epithelial cell survival. However, few studies have addressed the molecular mechanisms through which such important function is exerted. Fatty acid synthase (FASN), a key enzyme that synthesizes long-chain fatty acids and is involved in both embryogenesis and cancer, has been recently proposed as a direct target of p53 family members, including p63 and p73. Here we show that knockdown of either total or DeltaN-specific p63 isoforms in squamous cell carcinoma (SCC9) or immortalized prostate epithelial (iPrEC) cells caused a decrease in cell viability by inducing apoptosis without affecting the cell cycle. p63 silencing significantly reduced both the expression and the activity of FASN. Importantly, stable overexpression of either FASN or myristoylated AKT (myr-AKT) was able to partially rescue cells from cell death induced by p63 silencing. FASN induced AKT phosphorylation and a significant reduction in cell viability was observed when FASN-overexpressing SCC9 cells were treated with an AKT inhibitor after p63 knockdown, indicating that AKT plays a major role in FASN-mediated survival. Activated AKT did not cause any alteration in the FASN protein levels but induced its activity, suggesting that the rescue from apoptosis documented in the p63-silenced cells expressing myr-AKT cells may be partially mediated by FASN. Finally, we demonstrated that p63 and FASN expression are positively associated in clinical squamous cell carcinoma samples as well as in the developing prostate. Taken together, our findings demonstrate that FASN is a functionally relevant target of p63 and is required for mediating its pro-survival effects.
Sabbisetti
Venkata
V
Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Di Napoli
Arianna
A
Seeley
Apryle
A
Amato
Angela M
AM
O'Regan
Esther
E
Ghebremichael
Musie
M
Loda
Massimo
M
Signoretti
Sabina
S
D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells; D064429:Fatty Acid Synthases / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009227:Myristic Acids / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009227:Myristic Acids; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D064429:Fatty Acid Synthases