Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

Abstract

Zinc is vital for the structure and function of~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

Relationships of the Trace Elements Zinc and Magnesium With Diabetic Nephropathy-Associated Renal Functional Damage in Patients With Type 2 Diabetes Mellitus

“…Zn directly inhibits IKK via the thiol reaction. Thus, Zn can negatively regulate NF-κB pathways (30)(31)(32). Thirdly, serum Zn affects the expression of the Zn-finger protein A20.…”

Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family

“…More specifically, various ZnTs have been implicated in neurodegenerative diseases and cancers. Both a loss of function [ 43 ] and an over-expression of ZnT1 [ 44 ] for example, are associated with cancer, but that the former findings may be predictive or prognostic indicator of patient survivability [ 43 ]. Mutations in ZnT2 cause zinc concentrations in breast milk to be deficient, which leads to zinc deficiency in children if their primary source of the micronutrient comes from breast milk [ 45 ].…”

Metallothionein isoforms as double agents – Their roles in carcinogenesis, cancer progression and chemoresistance

“…In contrast, apo-MT-1 directly interacts with p53 to modulate Zn levels and p53 function. The p53 tumor suppressor tetramer requires certain levels of Zn ++ for proper folding of its DNA-binding domain (Lehvy et al, 2019). This modulation has been proven by the inactivation of p53 in the presence of highly expressed MT-1 and in the presence of apo-MT-1.…”