Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice

Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana; Nimmakayala, Rama Krishna; Perumal, Naveenkumar; Pothuraju, Ramesh; Atri, Pranita; Mahapatra, Sidharth; Thapa, Ishwor; Talmon, Geoffrey A.; Smith, Lynette M.; Yu, Xinheng; Neelamegham, Sriram; Fu, Jianxin; Xia, Lijun; Ponnusamy, Moorthy P.; Batra, Surinder K.

doi:10.1053/j.gastro.2018.08.007

Cited by 65 publications

(93 citation statements)

References 47 publications

(49 reference statements)

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“…For example, it has been reported that disruption of either Cosmc or T-synthase equally induced aberrant O-glycosylation and significantly promoted malignant behaviors in pancreatic cancer. 18,19 Liu et al also showed that Cosmc deficiency in human colorectal cancer cells markedly enhanced cellular growth and metastasis. 41 Conversely, several recent studies unexpectedly found that loss of T-synthase, but not Cosmc, resulted in Tn antigen expression and subsequently delayed tumor development including breast, head and neck, and hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 98%

“…15,16 However, the precise role of Tn antigen (representative of abnormal O-glycosylation) in tumor progression, particularly breast cancer, is largely unclear. The prevailing studies supported a tumorpromoting role for aberrant O-glycosylation in a broad range of human cancers, including pancreatic, colorectal, and gastric cancer, [17][18][19][20] whereas several recent reports indicated rather an opposite effect of aberrant O-glycosylation, which was shown to delay tumor development in breast, liver, and head and neck cancers. [21][22][23] Overall, there is much to be learned about the impact of aberrant O-glycosylation on breast cancer development.…”

Section: Introductionmentioning

confidence: 98%

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<p>Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44</p>

Du¹,

Jia²,

Dong³

et al. 2020

CMAR

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Background: Breast cancer remains the most lethal malignancy in women worldwide. Aberrant O-glycosylation is closely related to many human diseases, including breast carcinoma; however, its precise role in cancer development is insufficiently understood. Cosmc is an endoplasmic reticulum-localized chaperone that regulates the O-glycosylation of proteins. Cosmc dysfunction results in inactive T-synthase and expression of truncated O-glycans such as Tn antigen. Here we investigated the impact of Cosmc disruption-mediated aberrant O-glycosylation on breast cancer cell development through in vitro and in vivo experiments. Materials and Methods: We deleted the Cosmc gene in two breast cancer cell lines (MCF7, T47D) using the CRISPR/Cas-9 system and then measured the expression levels of Tn antigen. The proliferation of Tn-positive cells was examined by RTCA, colony formation and in vivo experiments. The effects of Cosmc deficiency on glycoprotein CD44 and MAPK pathway were also determined. Results: Both in vitro and in vivo studies showed that Cosmc deficiency markedly suppressed breast cancer cell growth compared with the corresponding controls. Mechanistically, Cosmc disruption impaired the protein expression of CD44 and the associated MAPK signaling pathway; the latter plays a crucial role in cell proliferation. Reconstitution of CD44 substantially reversed the observed alterations, confirming that CD44 requires normal O-glycosylation for its proper expression and activation of the related signaling pathway. Conclusion: This study showed that Cosmc deficiency-mediated aberrant O-glycosylation suppressed breast cancer cell growth, which was likely mediated by the impairment of CD44 expression.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

<p>Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44</p>

Du¹,

Jia²,

Dong³

et al. 2020

CMAR

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“…We recently published a role of C1GALT1 in pancreatic ductal carcinoma using in vitro and in vivo KO models [35]. The deletion of C1GALT1 caused an aggressive phenotype in the context of pancreatic ductal adenocarcinoma.…”

Section: Core-1 Synthase Loss Aggravates Pancreatic Cancermentioning

confidence: 99%

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

Gupta

Leon

Rauth

et al. 2020

Cells

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Glycosylation is the most commonly occurring post-translational modifications, and is believed to modify over 50% of all proteins. The process of glycan modification is directed by different glycosyltransferases, depending on the cell in which it is expressed. These small carbohydrate molecules consist of multiple glycan families that facilitate cell–cell interactions, protein interactions, and downstream signaling. An alteration of several types of O-glycan core structures have been implicated in multiple cancers, largely due to differential glycosyltransferase expression or activity. Consequently, aberrant O-linked glycosylation has been extensively demonstrated to affect biological function and protein integrity that directly result in cancer growth and progression of several diseases. Herein, we provide a comprehensive review of several initiating enzymes involved in the synthesis of O-linked glycosylation that significantly contribute to a number of different cancers.

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“…Aberrant glycosylation is associated with tumor initiation, development, and metastasis. The expression of TACAs like Tn, sTn, T, sT (truncated) and sialyl Lewis a (sLe a ), sialyl Lewis x (sLe x ) (de novo; neo-synthesis) are especially implicated in tumor formation and metastasis in many cancers, including PC [ 15 – 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Expression of truncated O -glycans induced oncogenic signaling in PC; however, expression of core-3 derived O -glycans (extended structures) was shown to inhibit tumor growth and metastasis [ 18 , 19 ]. In our recent study, we demonstrated that the crossing of C1galt1 floxed mice with Kras G12D ; p53 R172H ; Pdx-1-Cre mice resulted in elevated synthesis of truncated O -linked glycans promoting development of aggressive PDAC with increased metastasis [ 17 ]. De-regulated mucin expression (MUC1, MUC4, MUC5AC, MUC16; majorly O -linked glycoprotein) has been implicated in PC development, metastasis, and chemoresistance [ 16 , 20 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

et al. 2018

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BackgroundGlycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs.MethodsEffect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of KrasG12D; Pdx-1-Cre (KC) and KrasG12D; p53R172H; Pdx-1-Cre (KPC) tumors by immunofluorescence. Transient and CRISPR/Cas9 silencing of GALNT3 and B3GNT3 was performed to examine their effect on CSCs maintenance.ResultsInhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co-expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs.ConclusionsTaken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5074-2) contains supplementary material, which is available to authorized users.

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Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice

Cited by 65 publications

References 47 publications

<p>Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44</p>

<p>Cosmc Disruption-Mediated Aberrant O-glycosylation Suppresses Breast Cancer Cell Growth via Impairment of CD44</p>

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

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

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