SLC39A5 promotes the malignant progression of gastric cancer by activating BATF phosphorylation.

Abstract

Despite advances in diagnostic and therapeutic methods for gastric cancer (GC), early detection continues to be a significant challenge, resulting in late-stage diagnoses and poor survival outcomes. Studies have shown that solute carrier family 39 member 5 (SLC39A5) is upregulated in GC and may serve as a potential prognostic biomarker. However, the exact role of SLC39A5 and its underlying mechanisms remains unclear. To evaluate cell proliferation, migration, and invasion, a variety of assays, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, scratch, and Transwell assays, were conducted. The molecular interactions among genes were investigated through co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual luciferase reporter assays. An in vivo GC mouse model was established to substantiate our in vitro findings. Knockdown of SLC39A5 inhibited GC cell proliferation, migration, and invasion. Furthermore, SLC39A5 increased Moloney murine leukemia virus 1 (PIM1) kinase activity by enhancing zinc influx, which in turn triggered basic leucine zipper ATF-like transcription factor (BATF) phosphorylation and stabilized BATF protein. BATF overexpression reversed the inhibitory effect of SLC39A5 depletion on the behavior of GC cells and tumor growth. Moreover, we found that BATF, combined with the jun proto-oncogene, AP-1 transcription factor subunit (JUN), led to the suppression of huntingtin interacting protein 1-related (HIP1R) expression and the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In conclusion, SLC39A5 promotes the progression of GC via the BATF/HIP1R axis, which suggests that SLC39A5 acts as a therapeutic or diagnostic target for GC.