Investigating the Role of SLC35B4 in Colorectal Cancer Cells Under Normal and High Glucose Conditions

Abstract

Type 2 diabetes mellitus (T2DM) is a rapidly growing metabolic disorder associated with an increased risk of multiple cancers, including colorectal cancer (CRC), with hyperglycemia-driven metabolic reprogramming playing a central role in tumor progression. Emerging evidence suggests that this association is mediated not only by shared risk factors but also by underlying metabolic and molecular mechanisms. Among these, the hexosamine biosynthesis pathway (HBP) and aberrant protein glycosylation have been proposed as critical links between chronic hyperglycemia and tumor progression. Although epidemiological evidence suggests an association between the two diseases, the molecular link remains unclear and requires further investigation. SLC35B4 encodes a solute carrier protein involved in nucleotide sugar transport. More specifically, it transfers two major nucleotide sugars, UDP-xylose and UDP-N-acetylglucosamine (UDP-GlcNAc), into the lumen of the endoplasmic reticulum and Golgi apparatus. UDP-GlcNAc is the product of the HBP and serves as a substrate for O-GlcNAcylation, a post-translational modification that occurs in the cytoplasm and nucleus. SLC35B4, which regulates the intracellular distribution of UDP-GlcNAc, has recently gained attention as a potential mediator at the interface of metabolism and oncogenesis. This study aimed to investigate the role of SLC35B4 in CRC under varying glucose conditions, modeling normoglycemic and hyperglycemic environments. Human HT-29 CRC cells were subjected to siRNA-mediated knockdown of SLC35B4 and cultured under normal-glucose (NG; 5.5 mM) and high-glucose (HG; 25 mM) conditions. Functional assays, including wound-healing migration, MTT-based metabolic activity, and clonogenic assays, were performed to assess cellular behavior. Our findings revealed that SLC35B4 knockdown showed glucose-dependent effects in HT-29 CRC cells. Under NG conditions, SLC35B4 silencing increased cell migration and MTT-based metabolic activity. Under HG conditions, SLC35B4 knockdown reduced MTT-based metabolic activity without further increasing migration. Colony formation was not markedly affected. These findings suggest that SLC35B4 may regulate CRC cell behavior differently depending on glucose availability, highlighting its potential role in diabetes-associated CRC.