Data from Identification of <i>LIV1</i>, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Abstract

<div>Abstract<p>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 <i>LIV1</i>, a putative zinc transporter. <i>LIV1</i> is significantly induced by treatment with HDACi in a number of tumor cells, but not in normal cells. Knockdown of <i>LIV1</i> suppressed apoptosis induced by HDACi in tumor cells. Although HDACi induced a slight increase in the free intracellular zinc concentration, knockdown of <i>LIV1</i> 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 <i>LIV1</i>. However, the biological effects of TPEN were abolished by addition of physiologic concentrations of zinc. Taken together, the present study identifies <i>LIV1</i> as a critical mediator responsible for HDACi-induced apoptosis. The effect of <i>LIV1</i> 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. [Mol Cancer Ther 2009;8(11):3108–16]</p></div>