SLC41A2 Suppresses Colon Cancer Progression by Inhibiting GSK3β Ubiquitin-proteasome Degradation.

Background: Colon cancer is a highly prevalent tumor with a high mortality rate worldwide. SLC41A2 is a member of the solute carrier family, but its role in colon cancer is still unclear.

Methods: The relationship between the expression level of SLC41A2 and clinicopathological features in colon cancer was investigated using data from the TCGA database. The differential expression genes of SLC41A2 were identified the potential role of SLC41A2 in colon cancer was analysed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. By transfecting plasmids or siRNA to overexpress or knock down SLC41A2 in colon cancer cells, the effects of SLC41A2 on colon cancer cell proliferation, migration, and apoptosis were detected through EdU, MTT, wound-healing, Transwell, and JC-1 experiments. Western blot and ubiquitination experiments validated the regulation of GSK3β stability by SLC41A2. Rescue experiments and CCK8 assays confirmed the regulatory effect of SLC41A2 on GSK3β.

Results: Compared to normal tissues, SLC41A2 exhibited a lower expression level in colon cancer, and the expression levels of SLC41A2 were correlated with the stage and Tumor Node Metastasis (TNM) classification. GO and KEGG analyses displayed that SLC41A2 primarily affected the growth factor activity and Wnt signaling pathway. Furthermore, elevated expression of SLC41A2 notably decreased the proliferation, migration and invasion of colon cancer cells, along with increased apoptosis. The overexpression of SLC41A2 and rescue experiments confirmed that SLC41A2 enhances the protein stability of GSK3β by inhibiting its ubiquitin-proteasome degradation and causes the upregulation of GSK3β, thereby suppressing the progression of colon cancer.

Conclusion: SLC41A2 was lowly expressed in colon cancer tissues or cells. By inhibiting the ubiquitin-proteasome degradation of GSK3β, SLC41A2 can significantly upregulate the expression of GSK3β, which ultimately suppresses the proliferation and migration of colon cancer cells.