Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-<i>O</i>-Glycan to Cancer Cells

Tsai, Chin Hsien; Tzeng, Sheue Fen; Chao, Tai-Kuang; Tsai, Chia Yun; Yang, Yu; Lee, Ming Ting; Hwang, Juey Jen; Chou, Yu Ching; Tsai, Meng-Tsan; Lung, Tai; Hsiao, Pei Wen

doi:10.1158/0008-5472.can-16-0641

Cited by 56 publications

(57 citation statements)

References 31 publications

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“…1A, B). In line with this finding, up-regulated galectin-4 and C1GALT1 expression was also observed during the progression of the CRPC cell line 22Rv1 into metastatic 22Rv1-M4 cells, which were derived from in vivo lymph node metastases and exhibited high levels of metastatic ability (26). Flow cytograms of lectin staining displayed a right-shift in the PNA and jacalin curves, which indicated a difference in cell-surface Oglycosylation in 22Rv1-M4 cells compared with their parental cells, whereas N-glycans that were stained by PHA-L lectin remained unaltered ( Fig.…”

Section: Systematic Analysis Of Glycogene Expression Reveals a Correlsupporting

confidence: 70%

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: Systematic Analysis Of Glycogene Expression Reveals a Correlsupporting

confidence: 70%

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

et al. 2018

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“…301,302 There is a very well-established literature supporting links between corrupted VDR signaling and colon cancer. 85,147,[303][304][305][306][307][308] Our pan-cancer analyses add to these findings, suggesting that loss of VDR-induced growth restraint may be more apparent in colon cancer than in other cancers where alterations are not apparent.…”

Section: Author Manuscriptsupporting

confidence: 56%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

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The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

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“…Tsai et al studied 22Rv1-derived sublines showing elevated expression of C1GALT1, ST3GAL1, and ST6GALNAC4, along with reduced expression of B3GNT6 (Core-3 synthase) and GCNT3 (Core-2 synthase) [51]. Because T-antigen-expressing glycoproteins act as receptors for galectin-4, they were the candidate glycoproteins studied in the progression of prostate cancer (PCa).…”

Section: Interaction Of Core-1 Synthase and Galectin In Prostate 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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Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-O-Glycan to Cancer Cells

Cited by 56 publications

References 31 publications

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

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

Vitamin D Receptor Signaling and Cancer

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

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