Universität zu Köln

Sauer, M., Schuldner, M., Hoffmann, N., Cetintas, A., Reiners, K. S., Shatnyeva, O., Hallek, M., Hansen, H. P., Gasser, S. and von Strandmann, E. P. (2017). CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells. Oncogene, 36 (7). S. 933 - 942. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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 E mu-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sauer, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuldner, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cetintas, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiners, K. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shatnyeva, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, H. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gasser, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Strandmann, E. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-239659
DOI:	10.1038/onc.2016.259
Journal or Publication Title:	Oncogene
Volume:	36
Number:	7
Page Range:	S. 933 - 942
Date:	2017
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-ASSOCIATED TRANSCRIPT-3; DNA-DAMAGE RESPONSE; UP-REGULATION; NK CELLS; LEUKEMIA-CELLS; NF-KB; RECEPTOR; ACTIVATION; MUTATIONS; INDUCTION Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23965