Role of HDAC3 on p53 Expression and Apoptosis in T Cells of Patients with Multiple Sclerosis

Abstract

BackgroundHistone deacetylase 3 (HDAC3) belongs to a family of proteins which plays an important role in protein acetylation, chromatin remodeling and transcription of genes, including those that are involved in cell proliferation and cell death. While increased expression of HDAC3 is seen in neoplastic cells, the role of HDAC3 in T cells and their role in autoimmune disease is not known.Methodology/Principal FindingsApplying Affymetrix GeneChip Human Gene 1.0 ST Array and the mixed effects model for gene set analysis, we compared gene expression profiles between multiple sclerosis (MS) patients and healthy controls (HC). Within the Apoptosis_GO gene set, the constitutive expression level of HDAC3 in peripheral blood mononuclear cell (PBMC) was significantly increased in MS patients when compared to controls. Following addition of trichostatin A (TSA), an inhibitor of HDAC3, we examined the expression of p53 by flow cytometry and p53 targeted genes by real time RT-PCR in MS and HC. Culture of PBMC with TSA resulted in increased expression of p53 in HC but not in MS patients. TSA treated T cells from MS patients also showed reduced sensitivity to apoptosis when compared to HC, which was independent of activation of p53 targeted pro-apoptotic genes.Conclusion/SignificanceMS patients, when compared to controls, show an increased expression of HDAC3 and relative resistance to TSA induced apoptosis in T cells. Increased expression of HDAC3 in PBMC of MS patients may render putative autoreactive lymphocytes resistance to apoptosis and thereby contribute to autoimmunity.

Histone/protein deacetylases and T-cell immune responses

“…68 HDACi ranging from pan-HDACi, such as TsA, 69,70 SAHA, 71 butyrate, 72 scriptaid, 70 trapoxin, 69 to class I-specific HDACi, such as MS-275, 73 and class II-specific HDACi, such as MC1575, 74 were all shown to up-regulate p21 in tumor cells, but less is known of their effects in normal lymphocytes. Human PBMCs incubated for 2 days with a high proapoptotic concentration of TsA showed a moderate increase in p21 mRNA expression, 75 but there were no data reported regarding the cell subsets involved. The finding that butyrate blocked the proliferation in primary cultures of both WT and p21-deficient cells 76 raises doubts as to the role of p21 in inhibition of T-cell divisions by HDACi.…”

Scriptaid, a Novel Histone Deacetylase Inhibitor, Protects Against Traumatic Brain Injury via Modulation of PTEN and AKT Pathway

“…The epigenetic influence of HDIs on gene expression make them a useful new class of pharmacological agents that could ameliorate various disease conditions. For example, HDIs also promote neuronal survival in ischemic injury, [14][15][16][17] multiple sclerosis [18,19], and Alzheimer's and Huntington's disease models [20][21][22][23][24]. These multiple roles of HDIs can be attributed to alterations in the expression of different gene sets by increasing acetylation of chromatin.…”

The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

“…In recent years, accumulative evidence has suggested that inhibition of HDACs leads to the expression of tumor suppressor genes, such as p21 (7,8), p27 (8,9), and p53 (7,10), therefore inducing cell cycle arrest and cell apoptosis (1,9). HDAC inhibitors are emerging as a new class of anticancer agents for the treatment of solid and hematological malignancies (6).…”