Histone deacetylase inhibitors (HDACI) show promise as chemotherapeutic agents and have been demonstrated to induce apoptosis of tumor cells. To gain a better understanding of the molecular basis for HDACI-induced apoptosis and directly identify the gene products which are essential for mediating the apoptosis-regulatory functions of HDACI, we employed the suppression of mortality by antisense rescue technique (SMART). This approach permits the isolation of apoptosis-associated genes based on their selective inactivation by overexpression of antisense cDNAs. Because the antisense mRNA inactivates gene expression of apoptosis-specific genes, transfected cells survive in the presence of apoptosis inducers. We isolated several genes associated with HDACI-induced mortality (GHIM). Here we characterized one of the GHIM cDNAs, GHIM-27. Sequence analysis suggests that the GHIM-27 product is identical to human zinc transporter LIV1. Further researches indicate that LIV1 is significantly induced by HDACI treatment in various cancer cell lines. Down-regulation of LIV1 confers a strong resistance against HDACI-induced apoptosis, which is caused at least in part by disregulation of intracellular zinc homeostasis. Together, these studies identify a zinc transporter gene LIV1 which is responsible for HDACI-induced apoptosis by using a genetic approach. This may provide a potentially important target for anticancer therapy.

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