l-Fucose increases the fucosylation of colorectal cancer cells via promoting the accumulation of serine

Abstract

Fucosylation, a kind of posttranslational modification, has been identified as a key regulator of health, with alterations in this process serving as an indicator of diseases such as colorectal cancer. L-Fucose, an essential substrate of fucosylation, was reported to possess anticancer potential and increase fucosylation. However, the association between its tumour-inhibitory effect and its ability to regulate fucosylation was not fully understood. Herein, we demonstrate that the simultaneous inhibitory effect of L-fucose on cancer cell growth and enhanced fucosylation occurred only in certain colorectal cancer cells (HCT-116 cells) but not in normal cells (HCoEpic cells), which may be related to the induction of pro-apoptotic fucosylated proteins by L-fucose in HCT-116 cells. RNA-seq analysis showed that upregulation of the transcription levels of serine biosynthesis genes (e.g. PSAT1) and decreased levels of genes involved in serine consumption with supplemental L-fucose were also unique to HCT-116 cells. Increased serine concentrations only in HCT-116 cells and increased α1,3/6-fucosylation in CRC cells induced by exogenous serine also verified that L-fucose enhanced fucosylation via promoting intracellular serine accumulation. Additionally, the knockdown of PSAT1 and serine-deficiency impaired fucosylation. Notably, PSAT1 knockdown weakened the inhibitory effect of L-fucose on cell proliferation and migration. Interestingly, simultaneous increased levels of α1,3/6-fucosylation and PSAT1 transcription were also identified in colorectal tumor tissues of CRC patients. Together, these results uncover a novel role of serine synthesis and PSAT1 in the regulation of fucosylation and provide insights into the potential application of L-fucose in CRC therapy.