title: A SUMOylation-dependent pathway regulates SIRT1 transcription and lung cancer metastasis.
abstract: BACKGROUND
  Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in lung cancer metastasis. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. The role of SIRT1 in lung cancer EMT is largely undefined.
  
  
  METHODS
  The effect of SIRT1 on migration of lung cancer cells was evaluated by wound healing assay in vitro and metastasis assay in nude mice in vivo. Protein expression in human lung cancers and cultured lung cancer cells was assessed by western blotting and immunohistochemistry. Interaction between protein and DNA was measured by chromatin immunoprecipitation assay. SIRT1 promoter activity was determined by reporter assay.
  
  
  RESULTS
  SIRT1 activation antagonized migration of lung cancer cells by suppressing EMT in vitro. Activation of SIRT1 by resveratrol also statistically significantly hampered (by 68.33%; P < .001, two-sided test) lung cancer cell metastasis in vivo. Hypoxia repressed SIRT1 transcription through promoting the competition between Sp1 and HIC1 on the SIRT1 proximal promoter in a SUMOylation-dependent manner. Disruption of SUMOylation by targeting either Ubc9 or PIASy restored SIRT1 expression in and favored an epithelial-like phenotype of cancer cells, thereby preventing metastasis. Decreased SIRT1 combined with elevated PIASy expression was implicated in more-invasive types of lung cancers in humans.
  
  
  CONCLUSIONS
  We have identified a novel pathway that links SIRT1 down-regulation to hypoxia-induced EMT in lung cancer cells and may shed light on the development of novel antitumor therapeutics.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Provincial Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Sun
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Junliang
authors.initials: J
authors.lastname: Chen
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dehennaut
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kahn-Perles
authors.forename: Dominique
authors.initials: D
authors.lastname: Leprince
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D058207:Sumoylation; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1