Histone deacetylase inhibitors (HDACi) show promise as a novel class of antitumoral agents and have shown the ability to induce apoptosis of
tumor cells. To gain a better understanding of the action of HDACi, we conducted a functional gene screen approach named suppression of mortality by antisense rescue technique to identify the key genes responsible for the
tumor-selective killing
trichostatin A. Over 20 genes associated with HDACi-induced mortality were identified. One of the confirmed positive hits is LIV1, a putative
zinc transporter. LIV1 is significantly induced by treatment with HDACi in a number of
tumor cells, but not in normal cells. Knockdown of LIV1 suppressed apoptosis induced by HDACi in
tumor cells. Although HDACi induced a slight increase in the free intracellular
zinc concentration, knockdown of LIV1 significantly enhanced the intracellular
zinc level, which was associated with resistance to apoptosis. On the other hand, pretreatment of the cells with a specific
zinc chelator TPEN reversed the apoptosis resistance conferred by knockdown of LIV1. However, the
biological effects of
TPEN were abolished by addition of physiologic concentrations of
zinc. Taken together, the present study identifies LIV1 as a critical mediator responsible for HDACi-induced apoptosis. The effect of LIV1 is, at least in part, mediated by affecting intracellular
zinc homeostasis, which may be related to alteration of the catalytic activity of the
Caspase 3 and expression of some BCL-2 family genes. As such, these findings highlight a novel mechanism underlying the action of HDACi that could be potentially useful in the clinical setting.