title: Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis.
abstract: Natural killer (NK) cells are important effectors in the immune response to tumors. A number of cell-surface inhibitory and activating receptors on NK cells tightly regulate their interaction with target cell ligands. In particular, the strength of an anti-tumor immune response appears to depend critically on surface levels of one activating receptor, NKG2D. Correspondingly, expression of NKG2D ligands on target cells is a requirement for effective tumor immunosurveillance and the elimination of pathogen-infected cells. Sodium butyrate, a potent repressor of histone deacetylase (HDAC), has recently been proposed as a potential agent in cancer treatment based on its ability to modify, in several cancer cell types, the expression of a variety of genes related to cell cycle regulation and apoptosis. Here we report that, in the HeLa and HepG2 tumor cell lines, sodium butyrate upregulated the expression of the MHC class I-related chain molecules A and B (MICA and MICB) at both the mRNA and protein levels, resulting in an enhanced susceptibility of cells in both lines to NK lysis. It also led to an elevated expression of heat shock protein 70 (HSP70) and transcription factor Sp1, and increased the binding of transcription factors Sp1 and heat shock transcription factor 1 (HSF1) to the MICA/B promoter, resulting in increased expression of MICA and MICB. siRNA targeting Sp1 significantly attenuate the enhancement of MICA expression by sodium butyrate. These results suggest that sodium butyrate and other HDAC inhibitors may have therapeutic potential by enhancing the immune response to cancer.
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, China. caizhangsd@sdu.edu.cn
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D002087:Butyrates; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D014635:Valproic Acid