SIRT1 Regulates Endothelial Notch Signaling in Lung Cancer
Figure 5
A model for SIRT1-mediated regulation of endothelial DLL4/Notch signaling in lung cancer angiogenesis.
Our study show that the Delta-like ligand 4 (DLL4), which is highly expressed in vascular cells during tumor angiogenesis, binds to the Notch1 receptor and initiates proteolytic cleavages. The final intramembrane cleavage catalyzed by γ-secretase leads to the release of the active Notch1 intracellular domain (N1IC), which translocates into the nucleus and recruits the protein MAML1 and histone acetyltransferases (HATs, such as p300) to the CSL complex. This recruitment leads to the activation of the Notch1 target genes HEY1 and HEY2. Moreover, p300 acetylates N1IC and enhances its transcriptional activity whereas SIRT1 inhibits the acetylated form of N1IC and significantly diminishes N1IC activity induced by p300, thereby limiting the DLL4/Notch signaling response and inhibiting tumor angiogenesis.