Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells

Abstract

Histone deacetylase inhibitors (HDACi), including trichostatin A (TSA) and valproic acid, can alter the acetylation of histones in chromatin and enhance gene transcription. Previously we demonstrated that HDACi-treated tumor cells are capable of presenting antigen via the MHC class II pathway. In this study, we show that treatment with HDACi enhances the expression of molecules (TAP1, TAP2, LMP2, LMP7, Tapasin and MHC class I) involved in antigen processing and presentation via the MHC class I pathway in melanoma cells. HDACi treatment of B16F10 cells also enhanced cell surface expression of class I and costimulatory molecules CD40 and CD86. Enhanced transcription of these genes is associated with a significant increase in direct presentation of whole protein antigen and MHC class I-restricted peptides by TSA-treated B16F10 cells. Our data indicate that epigenetic modification can convert a tumor cell to an antigen presenting cell capable of activating IFN-γ secreting T cells via the class I pathway. These findings suggest that the abnormalities, observed in some tumors in the expression of MHC class I antigen processing and presentation molecules, may result from epigenetic repression.

Trichostatin A Sensitizes Hepatocellular Carcinoma Cells to Enhanced NK Cell-mediated Killing by Regulating Immune-related Genes

“…There are several recent reports that show an unexpected effect of TSA in regulating the immune system in various tumors (35,36). For example, HDACs are known to play critical roles in the immune escape mechanism of several tumor cells, such as melanoma cells and lymphoma cells (35,36). In melanoma cells (B16F10 cells), HDACs were shown to have a role in the reduction of MHC class I-associated antigen processing and presentation.…”

“…However, the effect of the immune system on tumor development is also important (31,32,33,34). There are several recent reports that show an unexpected effect of TSA in regulating the immune system in various tumors (35,36). For example, HDACs are known to play critical roles in the immune escape mechanism of several tumor cells, such as melanoma cells and lymphoma cells (35,36).…”

In situ analysis of the antigen-processing machinery in acute myeloid leukaemic blasts by tissue microarray

“…35,36 Treatment of AML with demethylating agents (for example, decitabine) and inhibitors of histone deacetylases (for example, valpronic acid) show potent antileukaemic effects. 37 In addition, these drugs have been shown to induce upregulation of APM components in various models, [38][39][40] which makes them an attractive tool to study mechanisms of APM dysregulation in AML.…”

The epigenetic regulation of Dicer and microRNA biogenesis by Panobinostat

“…6 Previous work from our lab demonstrated that HDACi treatment of tumor cells enhanced immune gene expression and tumor immunogenicity. [7][8][9][10][11] Identification of the mechanisms underlying immune modulation by HDACi treatment thus becomes an important question. A landmark study recently showed that a functional immune system is required for the beneficial effects of HDACi treatment.…”

“…23 One HDACi in particular, Panobinostat, has achieved some success in cancer and is FDA approved for treating multiple myeloma. 24 Panobinostat inhibits class I (HDAC 1, 2, 3, 8), class II (HDAC 4, 5,6,7,9), and class IV (HDAC 11) HDACs and is one of the most robust pan-HDACi used clinically. 25 However, it remains unknown if Panobinostat treatment affects Dicer and miR expression.…”