SIRT1 Regulates Endothelial Notch Signaling in Lung Cancer 英文参考文献.docVIP

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SIRT1 Regulates Endothelial Notch Signaling in Lung Cancer 英文参考文献.doc

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SIRT1 Regulates Endothelial Notch Signaling in Lung Cancer 英文参考文献

SIRT1RegulatesEndothelialNotchSignalinginLung Cancer MianXie1,2*,MingLiu1,2,Chao-ShengHe3 1China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, 2Guangzhou Institute of RespiratoryDisease,TheFirstAffiliatedHospitalofGuangzhouMedicalUniversity,Guangzhou,China,3DepartmentofInternalMedicine,GuangdongProvincialPeople’s Hospital,Guangzhou,China Abstract Background: Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein,wereportthatthenicotinamideadeninedinucleotide1(NAD1)-dependentdeacetylaseSIRT1canfunctionasan intrinsicnegativemodulatorofDelta-likeligand4(DLL4)/NotchsignalinginLewislungcarcinoma(LLC)xenograft-derived vascularendothelialcells(lungcancer-derivedECs). PrincipalFindings:SIRT1negativelyregulatesNotch1intracellulardomain(N1IC)andNotch1targetgenesHEY1andHEY2 in response to Delta-like ligand 4 (DLL4) stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitativechromatinimmunoprecipitation(qChIP)analysisandgenereporterassaydemonstratedthatSIRT1boundto one highly conserved region, which was located at approximately 2500bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/ NotchsignalingwasenhancedinSIRT1-silencedlungcancer-derivedECandrescuedbyNotchinhibitorDAPT.Invivo,an increaseinproangiogenicactivitywasobservedinMatrigelplugsfromendothelial-specificSIRT1knock-inmice.SIRT1also enhancedtumorneovascularizationandtumorgrowthofLLCxenografts. Conclusions:OurresultsshowthatSIRT1facilitatesendothelialcellbranchingandproliferationtoincreasevesseldensity and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targetingSIRT1activity