title: The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia.
abstract: OBJECTIVE
  Tumor hypoxia is associated with therapy resistance and malignancy. Previously we demonstrated that activation of autophagy and the unfolded protein response (UPR) promote hypoxia tolerance. Here we explored the importance of ULK1 in hypoxia tolerance, autophagy induction and its prognostic value for recurrence after treatment.
  
  
  METHODS
  Hypoxic regulation of ULK1 mRNA and protein was assessed in vitro and in primary human head and neck squamous cell carcinoma (HNSCC) xenografts. Its importance in autophagy induction, mitochondrial homeostasis and tolerance to chronic and acute hypoxia was evaluated in ULK1 knockdown cells. The prognostic value of ULK1 mRNA expression was assessed in 82 HNSCC patients.
  
  
  RESULTS
  ULK1 enrichment was observed in hypoxic tumor regions. High enrichment was associated with a high hypoxic fraction. In line with these findings, high ULK1 expression in HNSCC patients appeared associated with poor local control. Exposure of cells to hypoxia induced ULK1 mRNA in a UPR and HIF1α dependent manner. ULK1 knockdown decreased autophagy activation, increased mitochondrial mass and ROS exposure and sensitized cells to acute and chronic hypoxia.
  
  
  CONCLUSIONS
  We demonstrate that ULK1 is a hypoxia regulated gene and is associated with hypoxia tolerance and a worse clinical outcome.
authors.affiliation: Department of Radiation Oncology (Maastro Lab), GROW School for Oncology & Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors.forename: Marco B E
authors.initials: MB
authors.lastname: Schaaf
authors.forename: Dan
authors.initials: D
authors.lastname: Cojocari
authors.forename: Tom G
authors.initials: TG
authors.lastname: Keulers
authors.forename: Barry
authors.initials: B
authors.lastname: Jutten
authors.forename: Maud H
authors.initials: MH
authors.lastname: Starmans
authors.forename: Monique C
authors.initials: MC
authors.lastname: de Jong
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Begg
authors.forename: Kim G M
authors.initials: KG
authors.lastname: Savelkouls
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Marc
authors.initials: M
authors.lastname: Vooijs
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Kasper M A
authors.initials: KM
authors.lastname: Rouschop
mesh_terms: D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D056811:Unfolded Protein Response
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human
keywords: Autophagy; Hypoxia; ULK1; UPR