HDAC3 represses the expression of NKG2D ligands ULBPs in epithelial tumour cells: potential implications for the immunosurveillance of cancer

被引：0
作者：
A López-Soto
A R Folgueras
E Seto
S Gonzalez
机构：
[1] Universidad de Oviedo,Departamento de Biología Funcional
[2] IUOPA,Departamento de Bioquímica y Biología Molecular
[3] Universidad de Oviedo,undefined
[4] IUOPA,undefined
[5] H Lee Moffitt Cancer Center and Research Institute,undefined
来源：
Oncogene | 2009年 / 28卷
关键词：
ULBPs; NKG2D; HDAC3; tumour immunosurveillance;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The expression of the NKG2D ligands on cancer cells leads to their recognition and elimination by host immune responses mediated by natural killer and T cells. UL16-binding proteins (ULBPs) are NKG2D ligands, which are scarcely expressed in epithelial tumours, favouring their evasion from the immune system. Herein, we investigated the epigenetic mechanisms underlying the repression of ULBPs in epithelial cancer cells. We show that ULBP1–3 expression is increased in tumour cells after exposure to the inhibitor of histone deacetylases (HDACs) trichostatin A (TSA), which enhances the natural killer cell-mediated cytotoxicity of HeLa cells. Our experiments showed that the transcription factor Sp3 is crucial in the activation of the ULBP1 promoter by TSA. Furthermore, by small interfering RNA-mediated knockdown and overexpression of HDAC1–3, we showed that HDAC3 is a repressor of ULBPs expression in epithelial cancer cells. Remarkably, TSA treatment caused the complete release of HDAC3 from the ULBP1–3 promoters. HDAC3 is recruited to the ULBP1 promoter through its interaction with Sp3 and TSA treatment interfered with this association. Together, we describe a new mechanism by which cancer cells may evade the immune response through the epigenetic modulation of the ULBPs expression and provide a model in which HDAC inhibitors may favour the elimination of transformed cells by increasing the immunogenicity of epithelial tumours.
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页码：2370 / 2382
页数：12
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  • [1] Ammanamanchi S(2003)Acetylated sp3 is a transcriptional activator J Biol Chem 278 35775-35780
  • [2] Freeman JW(2007)Molecular regulation of MHC class I chain-related protein A expression after HDAC-inhibitor treatment of Jurkat T cells J Immunol 179 8235-8242
  • [3] Brattain MG(1991)A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells Nucleic Acids Res 19 2499-6329
  • [4] Andresen L(2005)Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate Cancer Res 65 6321-729
  • [5] Jensen H(1999)Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA Science 285 727-784
  • [6] Pedersen MT(2006)Anticancer activities of histone deacetylase inhibitors Nat Rev Drug Discov 5 769-5000
  • [7] Hansen KA(2001)Transcription factor Sp3 is regulated by acetylation Nucleic Acids Res 29 4994-133
  • [8] Skov S(2001)ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor Immunity 14 123-1657
  • [9] Andrews NC(2001)Duration of nuclear NF-kappaB action regulated by reversible acetylation Science 293 1653-1436
  • [10] Faller DV(2008)NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities Blood 111 1428-5511
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