Abstract
A SLC39A6 SNP is associated with shorter survival in esophageal squamous cell carcinoma.
Major finding: A SLC39A6 SNP is associated with shorter survival in esophageal squamous cell carcinoma.
Concept: A variant in the 5′ UTR may alleviate SLC39A6 repression and promote proliferation and invasion.
Impact: SLC39A6 may be a prognostic biomarker and therapeutic target in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) has a generally poor prognosis, but a high degree of heterogeneity in survival time has been observed. Wu and colleagues repurposed genome-wide association study (GWAS) data originally used to identify ESCC susceptibility loci in Chinese populations to determine if germline variation was associated with prognosis in patients for whom outcome information was available. Interestingly, a single-nucleotide polymorphism (SNP) within the 5′ untranslated region (UTR) of solute carrier family 39, member 6 (SLC39A6) was found to be associated with a shorter survival duration, and this finding was validated in 2 independent cohorts. The SNP associated with shorter survival disrupted protein binding at the SLC39A6 5′ UTR and drove high reporter gene expression in ESCC cells, suggesting that it disrupts a transcriptional repressor binding site within the SLC39A6 promoter. Consistent with these findings pointing to a role for SLC39A6 upregulation in ESCC, SLC39A6 mRNA and protein were overexpressed in the majority of ESCCs compared with matched normal esophageal epithelia, and high SLC39A6 protein expression was significantly correlated with short survival time in patients with advanced ESCC. Moreover, SLC39A6 expression promoted proliferation, migration, and invasion in ESCC cells, providing a potential explanation for why patients with ESCC carrying the allele associated with higher SLC39A6 expression did not survive as long as other patients. Although these findings were not adjusted for treatments such as chemotherapy or radiotherapy and remain to be confirmed in non-Chinese populations, these results suggest that SLC39A6 may be a prognostic indicator in ESCC. The fact that SLC39A6 encodes a zinc transporter also raises the possibility that targeted inhibition of SLC39A6 or modulation of intracellular zinc homeostasis may be effective in ESCC.