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Breast cancer is one of the most serious and deadly cancers in women worldwide, with distant metastases being the leading cause of death. Tn antigen, a tumor‐associated carbohydrate antigen, was frequently detected in breast cancer, but its exact role in breast cancer metastasis has not been well elucidated. Here we investigated the impact of Tn antigen expression on breast cancer metastasis and its underlying mechanisms. The expression of Tn antigen was induced in two breast cancer cell lines by deleting T‐synthase or Cosmc, both of which are required for normal O‐glycosylation. It showed that Tn‐expressing cancer cells promoted epithelial–mesenchymal transition (EMT) and metastatic features as compared to Tn(−) control cells both in vitro and in vivo. Mechanistically, we found that cancer susceptibility candidate 4 (CASC4), a heavily O‐glycosylated protein, was significantly downregulated in both Tn(+) cells. Overexpression of CASC4 suppressed Tn‐induced activation of EMT and cancer metastasis via inhibition of Cdc42 signaling. Furthermore, we confirmed that O‐glycosylation is essential for the functional role of CASC4 because defective O‐glycosylated CASC4 (mutant CASC4, which lacks nine O‐glycosylation sites) exerted marginal metastatic‐suppressing effects in comparison with WT CASC4. Collectively, these data suggest that Tn‐mediated aberrant O‐glycosylation contributes to breast cancer metastasis via impairment of CASC4 expression and function. [ABSTRACT FROM AUTHOR]

Cosmc is known as a T‐synthase‐specific molecular chaperone that plays a crucial role in the process of O‐glycosylation. Cosmc dysfunction leads to inactive T‐synthase and results in aberrant O‐glycosylation, which is associated with various tumour malignancies. However, it is unclear whether Cosmc has some other functions beyond its involvement in O‐glycosylation. In this study, we aimed to investigate the functional role of Cosmc in human colorectal cancer (CRC). We first assessed the expression levels of Cosmc in human CRC specimens and then forcedly expressed Cosmc in human CRC cell lines (HCT116, SW480) to examine its impact on cellular behaviours. The mechanisms for aberrant expression of Cosmc in CRC tissues and the altered behaviours of tumour cells were explored. It showed that the mRNA and protein levels of Cosmc were markedly elevated in human CRC specimens relative to normal colorectal tissues. The occurrence of endoplasmic reticulum (ER) stress may largely contribute to the increased Cosmc expression in cancer tissue and cells. Cosmc overexpression in CRC cells significantly promoted cell migration and invasion, which could be attributed to the activation of the epithelial‐mesenchymal transition (EMT) pathway rather than aberrant O‐glycosylation. These data indicate that Cosmc expression was elevated in human CRC possibly caused by ER stress, which further enhanced malignancies through the activation of EMT but independently of aberrant O‐glycosylation. [ABSTRACT FROM AUTHOR]

Tn antigen is a truncated O‐glycan, frequently detected in colorectal cancer (CRC), but its precise role in CRC metastasis is not well addressed. Here we investigated the effects of Core 1 β3Gal‐T specific molecular chaperone (Cosmc) deletion‐mediated Tn antigen exposure on CRC metastasis and its underlying mechanism. We first used CRISPR/Cas9 technology to knockout Cosmc, which is required for normal O‐glycosylation, and thereby obtained Tn‐positive CRC cells. We then investigated the biological consequences of Tn antigen expression in CRC. The results showed that Tn‐positive cells exhibited an enhanced metastatic capability both in vitro and in vivo. A further analysis indicated that Tn antigen expression induced typical activation of epithelial‐mesenchymal transition (EMT). Mechanistically, we found that H‐Ras, which is known to drive EMT, was markedly up‐regulated in Tn‐positive cells, whereas knockdown of H‐Ras suppressed Tn antigen induced activation of EMT. Furthermore, we confirmed that LS174T cells (Tn‐positive) transfected with wild‐type Cosmc, thus expressing no Tn antigen, had down‐regulation of H‐Ras expression and subsequent inhibition of EMT process. In addition, analysis of 438 samples in TCGA cohort demonstrated that Cosmc expression was reversely correlated with H‐Ras, underscoring the significance of Tn antigen‐H‐Ras signalling in CRC patients. These data demonstrated that Cosmc deletion‐mediated Tn antigen exposure promotes CRC metastasis, which is possibly mediated by H‐Ras‐induced EMT activation. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant O‐glycosylation is frequently observed in colorectal cancer (CRC) patients, but it is unclear if it contributes intrinsically to tumorigenesis. Here, we investigated the biological consequences of aberrant O‐glycosylation in CRC. We first detected the expression profile of Tn antigen in a serial of human CRC tissues and then explored the genetic and biosynthetic mechanisms. Moreover, we used a human CRC cell line (LS174T), which express Tn antigen, to assess whether aberrant O‐glycosylation can directly promote oncogenic properties. It showed that Tn antigen was detected in around 86% human primary and metastatic CRC tissues. Bio‐functional investigations showed that T‐synthase and Cosmc were both impaired in cancer tissues. A further analysis detected an occurrence of hypermethylation of Cosmc gene, which possibly caused its loss‐of‐function and a consequent inactive T‐synthase. Transfection of LS174T cells with WT Cosmc restored mature O‐glycosylation, which subsequently down‐regulated cancer cell proliferation, migration and apoptotic‐resistant ability. Significantly, the expression of MUC2, a heavily O‐glycosylated glycoprotein that plays an essential role in intestinal function, was uniformly reduced in human CRC tissues as well as in LS174T cells. These data suggest that aberrant O‐glycosylation contributes to the development of CRC through direct induction of oncogenic properties in cancer cells. [ABSTRACT FROM AUTHOR]