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Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis

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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.

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Abbreviations

NK:

Natural killer

CTL:

Cytotoxic T lymphocytes

NKG2D:

Natural killer group 2D

NKG2A:

Natural killer group 2A

IFN:

Interferon

MIC:

MHC class I-related chain

sMICA:

Soluble MICA

MHC:

Major histocompatibility complex

ULBP:

UL16-binding proteins

HSF1:

Heat shock factor 1

HSE:

Heat shock element

Sp1:

Specificity protein 1

HDAC:

Histone deacetylase

HATs:

Histone acetyltransferases

SB:

Sodium butyrate

VPA:

Sodium valproate

HSP:

Heat shock protein

TSA:

Trichostatin A

ChIP:

Chromatin immunoprecipitation

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Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (No. 30371302, No. 30671901, No. 30628014, and No. 90713033) and the Major State Basic Research Development Program of China (973 Program) (No. 2004CB518807, No. 2006CB504300, and No. 2007CB815800).

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Authors and Affiliations

  1. Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan, 250012, China

    Cai Zhang, Yiping Wang, Zhixia Zhou, Jian Zhang & Zhigang Tian

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  1. Cai Zhang
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Correspondence to Cai Zhang or Zhigang Tian.

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Zhang, C., Wang, Y., Zhou, Z. et al. Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis. Cancer Immunol Immunother 58, 1275–1285 (2009). https://doi.org/10.1007/s00262-008-0645-8

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