title: Notch1 binds and induces degradation of Snail in hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. We previously reported that the aberrant expression of Snail via activation of reactive oxygen species contributes to the invasive property of HCC, in part by downregulation of E-cadherin through both transcriptional repression and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in this context, we set out to look for other interactions that could affect its ability to promote oncogenic transformation and cancer cell invasion.
  
  
  RESULTS
  Using cells that stably expressed Snail, we characterized Snail protein interactors by tandem affinity purification and mass spectrometry. Immunoprecipitation and subcellular colocalization studies were performed to confirm our identification of the Notch1 intracellular domain (NICD) as a novel Snail-binding partner. NICD interaction with Snail was found to induce ubiquitination and MDM2-dependent degradation of Snail. Interestingly, NICD inhibited Snail-dependent invasive properties in both HCC cells and mouse embryonic fibroblasts.
  
  
  CONCLUSIONS
  Our study demonstrates that NICD can oppose Snail-dependent HCC cell invasion by binding and inducing proteolytic degradation of Snail. Although Notch signaling and Snail are both widely considered tumor-promoting factors, our findings indicate that the individual oncogenic contribution of Notch1 and Snail in malignant systems should be interpreted carefully, particularly when they are conjointly expressed.
authors: Department of Biological Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-747, Korea.
authors: Seung-Oe
authors: SO
authors: Lim
authors: Hyeon Seop
authors: HS
authors: Kim
authors: Xiaoyuan
authors: X
authors: Quan
authors: Sun-Min
authors: SM
authors: Ahn
authors: Hongtae
authors: H
authors: Kim
authors: David
authors: D
authors: Hsieh
authors: Je Kyung
authors: JK
authors: Seong
authors: Guhung
authors: G
authors: Jung
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000032:analysis / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D016335:Zinc Fingers
chemical_list: D051881:Receptor, Notch1; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors