Dietary palmitic acid inhibits colorectal cancer progression through enhancing bisecting GlcNAc

Area of Science:

• Oncology
• Glycobiology
• Nutritional Science

Background:

• Aberrant glycosylation, particularly bisecting N-acetylglucosamine (GlcNAc), is implicated in colorectal cancer (CRC) development.
• The enzyme MGAT3 catalyzes bisecting GlcNAc, but its role and regulation in CRC are not fully understood.
• The influence of dietary fatty acids, like palmitic acid (PA), on glycosylation in CRC remains largely unexplored.

Purpose of the Study:

• To investigate the role of bisecting GlcNAc and MGAT3 in colorectal cancer (CRC).
• To determine the impact of dietary palmitic acid (PA) on CRC progression and glycosylation.
• To elucidate the molecular mechanisms linking dietary PA, glycosylation, and CRC carcinogenesis.

Main Methods:

• Analysis of bisecting GlcNAc and MGAT3 levels in human CRC tissues and cell lines.
• Assessment of cell proliferation, migration, invasion, and apoptosis in CRC cells with altered bisecting GlcNAc levels.
• Utilizing azoxymethane/dextran sodium sulfate-induced CRC mouse models, including Mgat3-deficient mice, to evaluate the effects of a PA-rich diet.
• Intact glycopeptide analysis to identify PA-modified glycoproteins, followed by investigation of the EGFR/AKT signaling pathway.

Main Results:

• Decreased bisecting GlcNAc and MGAT3 levels were observed in human CRC tissues.
• Reduced bisecting GlcNAc in CRC cells correlated with increased proliferation, migration, invasion, and decreased apoptosis.
• A PA-rich diet suppressed CRC development in mice by upregulating bisecting GlcNAc, an effect dependent on MGAT3.
• Palmitic acid (PA) was found to enhance bisecting GlcNAc modification on desmoglein 2 (DSG2), which inhibits CRC carcinogenesis via the EGFR/AKT pathway.

Conclusions:

• Dietary palmitic acid (PA) exerts a protective effect against colorectal cancer (CRC) carcinogenesis.
• This suppression is mediated by PA-induced enhancement of bisecting N-acetylglucosamine (GlcNAc) modification on desmoglein 2 (DSG2).
• The findings establish a direct mechanistic link between dietary fatty acids and CRC suppression through specific glycosylation patterns.