title: EGFR cooperates with glucose transporter SGLT1 to enable chromatin remodeling in response to ionizing radiation.
abstract: OBJECTIVE
  EGFR and the sodium-dependent glucose transporter, SGLT1, are found in complex after radiation treatment. The aim of this study was to elucidate the role of EGFR in glucose uptake and chromatin remodeling.
  
  
  METHODS
  Glucose accumulation was quantified with help of (3)H-glucose. Involvement of SGLT was detected by a specific inhibitor. Role of EGFR was proved by EGFR overexpression and siRNA driven knockdown. Functional endpoints were intracellular ATP levels, protein expression, residual DNA-damage and colony formation.
  
  
  RESULTS
  EGFR/SGLT1 interactions in response to ionizing radiation were associated with increased glucose uptake. Nevertheless, tumor cells exhibit ATP depletion following irradiation. Recovery from radiation-induced ATP crisis was EGFR/SGLT-dependent and associated with increased cell survival and improved DNA-repair. The blockage of either EGFR or SGLT inhibited ATP level recovery and histone H3 modifications crucial for both chromatin remodeling and DNA repair in response to irradiation. Inhibition of the acetyltransferase TIP60, which is essential for histone H3-K9 acetylation and ATM activation, prevented energy crisis and chromatin remodeling.
  
  
  CONCLUSIONS
  Radiation-associated interactions between SGLT1 and EGFR resulted in increased glucose uptake, which counteracts the ATP crisis in tumor cells due to chromatin remodeling. The blockage of recovery from ATP crisis led to radio-sensitization in tumor cells.
authors.affiliation: Division of Radiobiology and Molecular Environmental Research, University of Tuebingen, Germany. klaus.dittmann@uni-tuebingen.de
authors.forename: Klaus
authors.initials: K
authors.lastname: Dittmann
authors.forename: Claus
authors.initials: C
authors.lastname: Mayer
authors.forename: H Peter
authors.initials: HP
authors.lastname: Rodemann
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000528:radiation effects*; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D010695:Phlorhizin / Q000494:pharmacology; D051269:Sodium-Glucose Transporter 1 / Q000502:physiology*
chemical_list: C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D000255:Adenosine Triphosphate; D010695:Phlorhizin; D066246:ErbB Receptors; D005947:Glucose