Effect of SLC5A8 Missense Variants on Its Tumor-Suppressive Function

Background: Solute carrier family-5 member-8 (SLC5A8) serves as a plasma membrane transporter for monocarboxylates, such as lactate, butyrate, pyruvate, acetate, propionate, nicotinate, and β-hydroxybutyrate. SLC5A8 can suppress colorectal cancer (CRC), and its tumor-suppressive function is mainly associated with butyrate, propionate, and pyruvate, which inhibit histone deacetylase. Although SLC5A8 is an important tumor suppressor, the impact of SLC5A8 variants on its tumor-suppressive function have not been reported. In this study, we investigated the effects of SLC5A8 missense variants on the expression and tumor-suppressive function of the transporter using various in vitro assays. Methods: Common SLC5A8 missense variations were identified using data from the Database of Single-Nucleotide Polymorphisms of the National Center for Biotechnology Information. We generated HCT116 and DLD-1 cell lines stably overexpressing wild-type SLC5A8 or SLC5A8 variants. The effect of each variant on SLC5A8 expression was examined via immunoblotting. Finally, using colony-formation, wound-healing, and invasion assays, we investigated whether the decrease in SLC5A8 expression resulting from its variants could affect the tumor-suppressive function of the transporter. Results: We identified two common missense single-nucleotide polymorphisms of SLC5A8, Val193Ile (rs1709189) and Met490Ile (rs164365), and assembled two major haplotypes of SLC5A8. Among these haplotypes, haplotype 1 contained wild-type SLC5A8 mRNA sequences and H2 contained two variants: Val193Ile and Met490Ile. Val193Ile and H2 significantly decreased SLC5A8 expression. These variants significantly increased the proliferation, migration, and invasion abilities of CRC cells. Conclusion: Decreased SLC5A8 expression caused by missense SLC5A8 variants appeared to significant impair the tumor-suppressive function of the transporter.