Differential Effects of Histone Deacetylases on the Expression of NKG2D Ligands and NK Cell-Mediated Anticancer Immunity in Lung Cancer Cells.

Haeryung Cho,Woo-Chang Son,You-Soo Park,Jaeho Bae,Young-Shin Lee,Eun Jung Youn,Chi-Dug Kang

doi:10.3390/molecules26133952

Abstract

Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.

Highlights

It was observed that FK228, RGFP966, and PCI34051 selectively inhibited the class I histone deacetylases (HDACs)
The selective inhibitor MC1568 targets HDAC4/5, which are class IIa HDACs, whereas Tubacin is an inhibitor of HDAC6, which belongs to HDAC class IIb [16,17]
HDAC1/2 inhibitor, could induce exULBP3, ULBP2, andtested, MICB, only respectively. These results suggest that amongst thethe inhibitors pression that of were tested, only FK228, the HDAC1/2 inhibitor, could induce the expression of Molecules 2021, 26, x FOR PEER REVIEW

Summary

Introduction

It could be suggested that enhancing the activity of immune cells might improve the prognosis of patients with lung cancer [2]. It is known that NK cells are involved in the immune surveillance of cancer and that persistent NK cell activity is associated with a good prognosis for patients with lung cancer [3]. Natural killer group 2, member D (NKG2D) is one of the major activating receptors that is expressed by human NK cells and a few types of T cell; it transduces activating signals to immune cells upon binding to the NKG2D ligands on cancer cells [4]. A better understanding of the mechanisms underlying the regulation of NKG2D ligands might have implications for the development of therapeutic strategies that can increase the expression of NKG2D ligands to levels that are adequate for NK cell activation. Histone deacetylation is an epigenetic process that affects gene transcription, and was reported to be one of the key mechanisms regulating the transcription of genes encoding the NKG2D ligands [11]

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