title: CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells.
abstract: Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eμ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sauer
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schuldner
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hoffmann
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Cetintas
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: K S
authors.initials: KS
authors.lastname: Reiners
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Shatnyeva
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: H P
authors.initials: HP
authors.lastname: Hansen
authors.affiliation: Immunology Programme, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Gasser
authors.affiliation: Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.|Experimental Tumor Research, Center for Tumor Biology and Immunology, Clinic for Hematology, Oncology and Immunology, Philipps University, Marburg, Germany.
authors.forename: E P
authors.initials: EP
authors.lastname: von Strandmann
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527086:Klrk1 protein, mouse; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; C423230:ULBP2 protein, human; D050880:p300-CBP Transcription Factors