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In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Identification of LIV1, a putative zinc transporter gene responsible for HDACi-induced apoptosis, using a functional
Xiaoli Ma1, Quanfu Ma, Jia Liu
1Cancer Biology Research Center, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubai, China.
Abstract:
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.
Insights
Histone deacetylase inhibitors (HDACi) induce tumor cell death by activating LIV1, a zinc transporter. LIV1 regulates intracellular zinc levels, impacting apoptosis and offering potential clinical applications for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Histone deacetylase inhibitors (HDACi) are promising antitumoral agents that induce cancer cell apoptosis.
- Understanding the precise molecular mechanisms of HDACi action is crucial for optimizing their clinical use.
Purpose of the Study:
- To identify key genes mediating tumor-selective killing by HDACi, specifically trichostatin A.
- To elucidate the role of identified genes, particularly LIV1, in HDACi-induced apoptosis and intracellular zinc homeostasis.
Main Methods:
- Functional gene screen using suppression of mortality by antisense rescue technique.
- Gene knockdown of LIV1 and assessment of apoptosis induction by HDACi.
- Measurement of intracellular zinc concentrations and modulation with zinc chelators.
Main Results:
- Over 20 genes associated with HDACi-induced mortality were identified, including LIV1.
- LIV1 expression was significantly induced by HDACi in tumor cells but not normal cells.
- LIV1 knockdown enhanced intracellular zinc levels and conferred resistance to HDACi-induced apoptosis, which was reversed by zinc chelation.
Conclusions:
- LIV1 is a critical mediator of HDACi-induced apoptosis in tumor cells.
- LIV1's function involves regulating intracellular zinc homeostasis, influencing Caspase 3 activity and BCL-2 family gene expression.
- These findings reveal a novel mechanism of HDACi action with potential clinical relevance in cancer treatment.
