title: Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma.
abstract: OBJECTIVE
  Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear.
  
  
  METHODS
  By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP(S127A)), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients.
  
  
  RESULTS
  Human HCC cell lines and mouse hepatocytes that overexpress YAP(S127A) up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer.
  
  
  CONCLUSIONS
  The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Darjus Felix
authors: DF
authors: Tschaharganeh
authors: Xin
authors: X
authors: Chen
authors: Philipp
authors: P
authors: Latzko
authors: Mona
authors: M
authors: Malz
authors: Matthias Martin
authors: MM
authors: Gaida
authors: Klaus
authors: K
authors: Felix
authors: Sara
authors: S
authors: Ladu
authors: Stephan
authors: S
authors: Singer
authors: Federico
authors: F
authors: Pinna
authors: Norbert
authors: N
authors: Gretz
authors: Carsten
authors: C
authors: Sticht
authors: Maria Lauda
authors: ML
authors: Tomasi
authors: Salvatore
authors: S
authors: Delogu
authors: Matthias
authors: M
authors: Evert
authors: Biao
authors: B
authors: Fan
authors: Silvia
authors: S
authors: Ribback
authors: Lijie
authors: L
authors: Jiang
authors: Stefania
authors: S
authors: Brozzetti
authors: Frank
authors: F
authors: Bergmann
authors: Frank
authors: F
authors: Dombrowski
authors: Peter
authors: P
authors: Schirmacher
authors: Diego Francesco
authors: DF
authors: Calvisi
authors: Kai
authors: K
authors: Breuhahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D000072100:Jagged-1 Protein; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009124:Muscle Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*; D000072099:Serrate-Jagged Proteins; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse