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

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.

Valproic acid increases CAR T cell cytotoxicity against acute myeloid leukemia

“…[10][11][12] Furthermore, studies have indicated that only inhibition of HDAC1 and HDAC2 can effectively induce the expression of NKG2D ligands in lung cancer. 23 VPA was reported to inhibit the activity of HDAC1/2 in several diseases. 24 25 Moreover, Gottlicher et al found that VPA could cause hyperacetylation of the N-terminal tails of H3 and H4 histones by inhibiting the catalytic activity of class I HDACs and inducing proteasomal degradation of HDAC2 in the AML model.…”

Radiosensitization effect by HDAC inhibition improves NKG2D-dependent natural killer cytotoxicity in hepatocellular carcinoma

“…HDAC inhibitors have been reported to upregulate expression of NKG2D ligands, and enhance NK cell-mediated killing by regulating immune-related genes and chemokines responsible for the increased infiltration of NK cells into tumor tissues ( 11 , 26 , 27 ). RT increases the expression of NKG2D ligands in tumors, and regulates immune cells including NK cells by inducing the secretion of IFN-γ, TNF-α, perforin, and granzyme B of NK cells through the p38-MAPK, ATM, and NF-κB pathways ( 28 ).…”

Epigenetic remodeling of the immune landscape in cancer: therapeutic hurdles and opportunities

“…For instance, romidepsin increases MICA/B on AML cells, which in turn promotes antibody-dependent phagocytosis of AML cells by macrophages [ 152 ]. Romidepsin also induces NKG2D ligand expression on lung cancer cell lines and improves NK cell-mediated anti-cancer immunity [ 153 ]. Vorinostat upregulates OX40L in Hodgkin lymphoma cells.…”