Since ATX has been identified as the major source of serum and plasma lysophospholipase D (LPLD) activity, we extended our interests to include ATX substrates and products. Our group recently found that epigenetic agents (trichostatin A and 5-aza-2'-deoxycytodine) switch the ATX product sphingosine-1-phosphate (S1P) from an inhibitor to a stimulator of motility. Quantitative PCR revealed that the S1P receptor associated with inhibition of motility (S1P2) was downregulated, while the receptors associated with stimulation of motility (S1P1 and S1P3) were upregulated by these two agents. The effect of trichostatin A was readily reversible confirming that it did not result in a mutational effect, and 5-aza-2'-deoxycytidine caused demethylation of a putative S1P1 promoter. This was the first demonstration that this family of receptors (EDG receptors) could be susceptible to epigenetic regulation.Regulation of ATX expression is poorly understood. We collaborated in a study that compared breast cancer cells transfected with CST6 (candidate tumor suppressor-6) to mock-transfected cells. Elevated expression of CST6, which is expressed in normal breast epithelial but downregulated in breast cancer cells, was found to down-regulate the expression of ATX. We also participated in a study of ATX-transfected fibroblasts, which found that the presence of ATX and its substrate lysophosphatidylcholine prevented conditional apoptosis in fibroblasts. Because ATX plays a major role in regulating serum levels of lysophosphatidic acid (LPA), there has been great interest in finding ATX inhibitors. Our group previously found that L-histidine acts as a non-competitive, but non-specific, inhibitor of the LPLD activity of ATX. We recently collaborated in a study demonstrating that carba analogs of cyclic phosphatidic acid are selective inhibitors of ATX.
