Folate receptor β (FR-β) is highly expressed in placenta, mature neutrophils and activated monocytes and macrophages. Other normal tissues virtually lack FR-β. FR-β is also expressed in about 70% of acute myelogenious leukemias (AMLs) and chronic myelogenious leukemias (CMLs). FR-β is a promising target for therapeutic intervention in AML owing particularly to its specific up-regulation in AML cells by all-trans retinoic acid (ATRA). Here we show that the histione deacetylase (HDAC) inhibitors, Trichostatin A (TSA), valproic acid (VPA) and FK228 can synergize with ATRA to enhance FR-β induction in KG-1 and MV4-11 human AML cells. The synergistic effect occurred at the promoter level as seen in 293 cells stably transfected with an FR-β promoter-luciferase reporter construct. Further mechanistic studies showed that TSA enhanced the ATRA effect on FR-β expression by further changing the acetylation status of two core histones H3 and H4 in the Sp1 and AP1 regions of FR-β promoter. TSA also altered the association of retinoic acid receptors (RARs) with the FR-β promoter.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]