Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice

Song, Kai; Herzog, Brett H.; Fu, Jianxin; Sheng, Minjia; Bergstrom, Kirk; McDaniel, J. Michael; McGee, Samuel; Cai, Xiaofeng; Li, Ping; Chen, Hong; Xia, Lijun

doi:10.1074/jbc.m115.654483

Cited by 26 publications

(23 citation statements)

References 30 publications

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“…Up-regulated C1GALT1 is associated more with mCRPC than with localized tumors, which suggests that core 1 O-glycosylation may mediate the dissemination and adaptation of cancer cells to distant tissues. In line with this supposition, genetic deletion of C1galt1 in the mammary epithelium hampered carcinogenesis in the MMTV-PyMT mouse mammary tumor model (39). In colorectal tumors, increased C1GALT1 expression was associated with poor survival, whereas C1GALT1 overexpression modified O-glycans on fibroblast growth factor receptor 2 and enhances its phosphorylation, which promotes invasive behavior and stem-like properties in colon cancer cells (40).…”

Section: Discussionmentioning

confidence: 84%

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

et al. 2018

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Disseminated castration-resistant prostate cancer (CRPC) is a common disease in men that is characterized by limited survival and resistance to androgen-deprivation therapy. The increase in human epidermal growth factor receptor 2 (HER2) signaling contributes to androgen receptor activity in a subset of patients with CRPC; however, enigmatically, HER2-targeted therapies have demonstrated a lack of efficacy in patients with CRPC. Aberrant glycosylation is a hallmark of cancer and involves key processes that support cancer progression. Using transcriptomic analysis of prostate cancer data sets, histopathologic examination of clinical specimens, and in vivo experiments of xenograft models, we reveal in this study a coordinated increase in glycan-binding protein, galectin-4, specific glycosyltransferases of core 1 synthase, glycoprotein- N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) and ST3 beta-galactoside α-2,3-sialyltransferase 1 (ST3GAL1), and resulting mucin-type O-glycans during the progression of CRPC. Furthermore, galectin-4 engaged with C1GALT1-dependent O-glycans to promote castration resistance and metastasis by activating receptor tyrosine kinase signaling and cancer cell stemness properties mediated by SRY-box 9 (SOX9). This galectin-glycan interaction up-regulated the MYC-dependent expression of C1GALT1 and ST3GAL1, which altered cellular mucin-type O-glycosylation to allow for galectin-4 binding. In clinical prostate cancer, high-level expression of C1GALT1 and galectin-4 together predict poor overall survival compared with low-level expression of C1GALT1 and galectin-4. In summary, MYC regulates abnormal O-glycosylation, thus priming cells for binding to galectin-4 and downstream signaling, which promotes castration resistance and metastasis.-Tzeng, S.-F., Tsai, C.-H., Chao, T.-K., Chou, Y.-C., Yang, Y.-C., Tsai, M.-H., Cha, T.-L., Hsiao, P.-W. O-Glycosylation-mediated signaling circuit drives metastatic castration-resistant prostate cancer.

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Section: Discussionmentioning

confidence: 84%

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

et al. 2018

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“…These types of defects are indeed observed in some colon, blood, and pancreatic cancers (Ju et al, 2008;Mi et al, 2012). However, experimentally depleting C1GALT1 yields limited effects or reductions in tumor growth in various systems (Radhakrishnan et al, 2014;Song et al, 2015).…”

Section: Discussionmentioning

confidence: 96%

Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

et al. 2017

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Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.

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“…Conversely, Bergstrom and colleagues unexpectedly found that Tn antigen is not involved with cancer progression in a murine model of colorectal cancer; instead intestinal inflammation is a major mechanism responsible for tumour development . Song et al even reported that Tn antigen expression suppressed breast cancer development in mice via impairment of MUC1 expression, which is usually highly expressed in various cancers . All of these findings suggest that the role of Tn antigen in cancer progression and metastasis needs to be further understood.…”

Section: Discussionmentioning

confidence: 99%

“…37 Song et al even reported that Tn antigen expression suppressed breast cancer development in mice via impairment of MUC1 expression, which is usually highly expressed in various cancers. 38 All of these findings suggest that the role of Tn antigen in cancer progression and metastasis needs to be further understood.…”

Section: Discussionmentioning

confidence: 99%

Tn antigen promotes human colorectal cancer metastasis via H‐Ras mediated epithelial‐mesenchymal transition activation

Liu

Dong

et al. 2019

J Cellular Molecular Medi

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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 LS 174T 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.

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Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice

Cited by 26 publications

References 30 publications

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

O‐Glycosylation‐mediated signaling circuit drives metastatic castration‐resistant prostate cancer

Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis

Tn antigen promotes human colorectal cancer metastasis via H‐Ras mediated epithelial‐mesenchymal transition activation

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