ZIP11 is required for proliferation of HeLa cells

Zinc (Zn) is an essential trace element that plays a key role in several biological processes including transcriptional regulation, signaling, and catalysis. A subcellular network of transporters ensures adequate distribution of Zn to facilitate homeostasis. Among these are a family of importers, Zrt/Irt-like protein (ZIP), which consists of 14 members (ZIP1-ZIP14) that mobilize extracellular Zn into the cytosol. Expression of these transporters varies among tissues and during developmental stages. The presence of ZIP transporters at various cellular locations is essential for defining the net cellular transport of Zn. Normally, the ion is bound to proteins or sequestered in organelles and vesicles. Although research has focused on Zn internalization in mammalian cells, little is yet known about Zn mobilization within the organelles, including the nuclei, under both normal and pathological conditions. ZIP11 is the only ZIP transporter proposed to be localized to the nucleus of mammalian cells, yet no clear cellular role has been attributed to this protein. We hypothesized that ZIP11 is a nuclear Zn transporter essential to maintaining nuclear Zn homeostasis in mammalian cells. We utilized HeLa cells to test this hypothesis, as research in humans has identified an incidence of ZIP11 gain of function in cervical cancer patients that results in deleterious effects. Therefore, we stably knocked down ZIP11 in HeLa cancer cells and investigated the effect of Zn dysregulation in vitro. Our data show that ZIP11 KD reduced the proliferation of HeLa cells as a consequence of nuclear accumulation of Zn. RNA-seq analyses revealed that genes related to angiogenesis, apoptosis, mRNA metabolism, and the Notch signaling pathways are dysregulated. Consequently, ZIP11 KD HeLa cells have impaired migration and invasive properties and as well as decreased mitochondrial potential. These data suggest that deletion of this Zn importer lpoint to a novel mechanism whereby maintenance of nuclear Zn homeostasis is essential for cancer progression.