Over-expression of microRNA-494 is involved in repression of genes but independent of antigen receptor-mediated apoptosis in a T cell leukemia cell line (TECH1P.867)

Abstract

Abstract Treatment of the human T cell leukemia cell line, Jurkat with the histone deacetylase inhibitor, Trichostatin A (TSA) resulted in histone hyperacetylation, dissipation of mitochondrial transmembrane potential, and augmentation of T cell receptor mediated apoptosis. Global gene expression profiling of TSA-treated Jurkat cells revealed the repression of several genes involved in T cell receptor signaling and PVRIG, a non-coding member of the paired immune-like receptor family genes. Analysis of total RNA by qRT-PCR validated these findings. Genome wide microRNA expression profiling uncovered drug-mediated down-regulation of microRNAs, including the miR-17-92 cluster, critical for T cell biology. Notably, TSA treatment induced the up-regulation of miR-494, which correlated with Jurkat cell death. This is in stark contrast to previous reports indicating that the up-regulation of miR-494 is essential for the survival of carcinomas. Interestingly, transfection of Jurkat cells with a miR-494 inhibitor partially blocked TSA-mediated down-regulation of PVRIG expression, without abrogating the antigen receptor mediated apoptosis. These data demonstrate that the over-expression of miR-494 as a consequence of histone hyperacetylation results in tumor cell death, which is unrelated to antigen receptor-mediated apoptosis. Thus, up-regulation of miR-494 via epigenetic mechanisms appears to be a novel treatment strategy for T cell leukemia.