ZBTB16 upregulation maintains copper homeostasis to support esophageal tumor progression

Zinc finger and BTB domain‑containing protein 16 (ZBTB16) plays diverse roles in a number of different cancer types, but its function and mechanism in esophageal cancer remain ambiguous. The present study was, to the best of our knowledge, the first demonstration that ZBTB16 was highly expressed in esophageal cancer tissues and cell lines. Knockdown of ZBTB16 significantly inhibited the proliferation and migration of esophageal cancer cells. Furthermore, ZBTB16 silencing increased the rate of cell death in esophageal cancer cells and induced mitochondrial membrane potential loss, intracellular copper accumulation and elevated oxidative stress. Mechanistically, knockdown of ZBTB16 downregulated the expression of ATPase copper‑transporting α and ATPase copper‑transporting β (ATP7B), while upregulating copper uptake protein 1 and ferredoxin. The present study further demonstrated that ZBTB16 knockdown increased the production of reactive oxygen species, which was partially rescued by ATP7B overexpression. In a mouse xenograft model of esophageal cancer, ZBTB16 knockdown markedly suppressed tumor growth, significantly reduced tumor weight and volume and notably altered the expression of cuproptosis‑related proteins in vivo. Summarily, ZBTB16 promoted the development of esophageal cancer by regulating copper homeostasis and oxidative stress. Therefore, ZBTB16 may represent a potential therapeutic target for the treatment of esophageal cancer.