HDAC8, an evolutionarily distinct, X-linked, zinc-dependent class I histone/protein deacetylase, is implicated in developmental disorders, parasitic infections, myopathy, and cancers.
More...HDAC8, an evolutionarily distinct, X-linked, zinc-dependent class I histone/protein deacetylase, is implicated in developmental disorders, parasitic infections, myopathy, and cancers. Our study demonstrates a previously unknown role of HDAC8 in immune cells by conditional targeting of HDAC8 in murine T cells and application of selective HDAC8 inhibitors. Using flow cytometry, RNA-seq and ChIP-seq analyses, we demonstrate that knocking down or inhibiting HDAC8 impaired murine Treg suppressive function in vitro and in vivo, but promoted conventional host T cell responses, thereby limiting tumor growth. Mechanistically, HDAC8 knockout downregulated Foxp3 expression, enhanced H3K27ac acetylation levels and promoted IL-2, IL-6, Fas, and FasL expression in both Treg and conventional T-effector cells. Thus, our combined genetic and pharmacologic studies establish the central importance of HDAC8 in T cell responses and suggest that selective HDAC8 inhibitors represent a potential novel therapeutic approach in immuno-oncology.
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