Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity

Abstract

The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal-epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial-mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT-MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.

A Systematic Review on the Implications of O-linked Glycan Branching and Truncating Enzymes on Cancer Progression and Metastasis

“…However, this is the first instance to demonstrate the role of Core-3 synthase in colon cancer. Another study delineated the role of B3GNT6 in colon cancer [58]. A loss of B3GNT6 was associated with lymph node metastasis, distant metastasis, and poor OAS.…”

Robust Glycogene-Based Prognostic Signature for Proficient Mismatch Repair Colorectal Adenocarcinoma

“…Iwai et al (46) demonstrated that the expression of B3GNT6 is significantly decreased in CRC tissues and is a useful marker for distinguishing benign adenomas from premalignant lesions. Moreover, decreased expression of B3GNT6 is related to epithelial-mesenchymal transition (EMT) and metastasis in CRC (46)(47)(48), which provides evidence for the prognostic value of B3GNT6. In addition, GALNT3 has been shown to be regulated by the linc01296/miR-26a network in CRC (49).…”

Association between the expression of core 3 synthase and survival outcomes of patients with cholangiocarcinoma

“…Core 3-expressing prostate cancer cells were also found to decrease the activity of tumor formation and metastatic activity to the lymph nodes by attenuating the maturation and heterodimerization of integrin α2β1 (12). The core 3 structure was recently reported to be involved in EMT-MET regulation via the MUC1/p53/miR-200c signaling cascade (13).…”