title: PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells.
abstract: BACKGROUND
  The PIAS4 protein belongs to the family of protein inhibitors of activated STAT, but has since been implicated in various biological activities including the post-translational modification known as sumoylation. In this study, we explored the roles of PIAS4 in pancreatic tumourigenesis.
  
  
  METHODS
  The expression levels of PIAS4 in pancreatic cancer cells were examined. Cell proliferation and invasion was studied after overexpression and gene silencing of PIAS4. The effect of PIAS4 on hypoxia signalling was investigated.
  
  
  RESULTS
  The protein was overexpressed in pancreatic cancer cells compared with the normal pancreas. Gene silencing by PIAS4 small interfering RNA (siRNA) suppressed pancreatic cancer cell growth and overexpression of PIAS4 induced expression of genes related to cell growth. The overexpression of PIAS4 is essential for the regulation of the hypoxia signalling pathway. PIAS4 interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization, and impaired function. Pancreatic cancer cells (Panc0327, MiaPaCa2) treated with PIAS4 siRNA suppressed expression of the hypoxia-inducible factor hypoxia-inducible factor 1 alpha and its target genes JMJD1A, VEGF, and STAT3.
  
  
  CONCLUSIONS
  Our study elucidates the role of PIAS4 in the regulation of pancreatic cancer cell growth, where the suppression of its activity represents a novel therapeutic target for pancreatic cancers.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Level 12-01, Singapore 117599, Singapore.
authors.forename: W
authors.initials: W
authors.lastname: Chien
authors.forename: K L
authors.initials: KL
authors.lastname: Lee
authors.forename: L W
authors.initials: LW
authors.lastname: Ding
authors.forename: P
authors.initials: P
authors.lastname: Wuensche
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: N B
authors.initials: NB
authors.lastname: Doan
authors.forename: L
authors.initials: L
authors.lastname: Poellinger
authors.forename: J W
authors.initials: JW
authors.lastname: Said
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D015398:Signal Transduction; D058207:Sumoylation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein