Handbook of Glycosyltransferases and Related Genes
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This was found to be caused by the dysfunction of a key glucose transporter, GLUT2. Furthermore, a high-fat diet, an important causative factor of insulin resistance, downregulated GnT-IVa expression in the pancreas due to abnormal export of the key transcription factors forkhead box protein A2 FOXA2 and hepatocyte nuclear factor 1-alpha HNF1A from the nuclei [ 84 ].
In addition, human type 2 diabetic patients showed the decreased expression of GnT-IVa. These findings clearly show that the GnT-IVa enzyme is critically involved in glucose metabolism and the onset of diabetes. Considering that both galectin [ 85 ] and GnT-V discussed above are involved in cancer progression, cell-proliferating and invasive effects on cancer cells are also suggested for GnT-IV, similarly to GnT-V. This structure is abundant in N -glycans and plays critical roles in numerous physiological and pathological processes, including cancer development and therapeutics [ 87 ].
Fut8 is widely expressed in various mammalian tissues, except for liver [ 91 ] and like GnT-III, it is also aberrantly upregulated during hepatocarcinogenesis [ 92 ]. Moreover, the aberrant upregulation of FUT8 in non-small-cell lung cancer was reported to be correlated with the poor clinical outcomes [ 93 , 94 ], suggesting the involvement of Fut8 in cancer development and its potential as biomarker. As expected by the widespread expression and abundance of core fucose, Fut8 Fut8 -null mice show multiple phenotypes including semilethality [ 95 ], the development of emphysema [ 95 , 96 ], dysfunction in the brain [ 97 , 98 ] and impaired immunity [ 99 , ].
In addition, several reports have revealed that core fucose is required for growth factor-dependent cell proliferation in disease models such as lung cancer [ ] and liver regeneration [ ]. These findings strongly suggest that Fut8 promotes cancer growth.
In fact a recent report demonstrated that Fut8-null mice exhibited reduced cancer growth in a chemical-induced hepatoma model [ ]. Moreover, Fut8 or core fucose is aberrantly upregulated in several types of cancer in addition to hepatoma and lung cancer, such as breast [ ] and prostate cancers [ , ]. Core fucosylation has already been clinically applied as a biomarker for the detection of cancer.
Since Fut8 is aberrantly elevated in hepatocellular carcinoma compared with nearly no expression in normal liver, we can assume that liver-derived core fucosylated proteins in serum would be utilized for the diagnosis of liver cancer. In fact, fucosylated alpha-fetoprotein AFP , AFP-L3, has been developed as a biomarker and approved for the early detection of liver cancer [ ], being the most successful glyco-related cancer biomarker to date [ 2 , ].
AFP itself is an oncofetal protein and was first found to be a marker of hepatoma [ ]. However, the serum AFP level is also increased in other nonhepatoma diseases such as liver cirrhosis and acute and chronic hepatitis, which makes it difficult to diagnose primary hepatoma at an early stage using AFP alone.
AFP glycoforms can be separated by using a fucose-specific plant lectin, Lens culinaris agglutinin LCA , to give L1, L2 and L3 fractions and AFP-L3 is mostly expressed in the sera of primary hepatoma patients, but not in cases of liver cirrhosis.http://xn--27-jlceoalydfe0a7e.xn--p1ai/includes
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Our glycomic analysis revealed that L3 showed the highest level of core fucose among the three fractions [ ]. Furthermore, fucosylated haptoglobin was also identified as a marker for various types of cancer [ , ]. Our site-specific glycomic analysis revealed that both core fucose and Lewis types of fucose that is synthesized by other Futs expressed on haptoglobin, are increased in various cancers [ ]. Again, these results highlight the importance of core fucose for understanding the roles of glycans in liver cancer and their therapeutic applications.
The involvement of core fucose in antibody cancer therapy has also been reported. Antibody-dependent cellular cytotoxicity ADCC has a central role in cancer therapy using antibodies [ ]. Sialylation and bisecting GlcNAcylation of IgG-Fc have also been shown to have effects on its efficacy [ ] and N -glycan decoration is also known to be critical for the half-life in sera and the antigenicity of biopharmaceuticals [ ]. These results underscore the importance of N -glycan branching, especially core fucosylation, for effective and safe therapy using biopharmaceuticals.
Although the specific factors involved in transcriptional regulation of the genes encoding N -glycan branching enzymes are not well understood, some transcription factors were found to be critical for transcriptional activation of these genes in cancer cells. Our group independently found that the Ets-1 oncogenic transcription factor directly transactivates the MGAT5 promoter in human bile duct carcinoma cells [ ] and that the Ets-1 levels were highly correlated with the levels of GnT-V expression in various cancer cell lines [ ].
These reports suggest that the oncogenic Ets pathway is directly involved in GnT-V transactivation. Other transcription factors responsible for the regulation of N -glycan branching genes have also been reported, although their roles in oncogenesis are still not fully understood.
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Identification of the specific transcription factors for the oncogenic transcription of N -glycan branching genes is an interesting topic for future research. When considering the topic of genetic regulation of the N -glycan branching enzymes in cancer, epigenetic factors should not be overlooked. Epigenetics involves the structural adaptation of chromosomal regions beyond changes in DNA sequence and numerous cancerous changes in gene transcription and genome organization have been shown to be highly dependent on epigenetic mechanisms [ , ].
We here focus on how N -glycan branching genes are epigenetically regulated in cancer, particularly by DNA methylation, histone modifications and miRNAs. DNA methylation often occurs at CpG sites and methylation of a CpG cluster at an upstream promoter region CpG island is well known to silence gene transcription [ ]. The methylation of a CpG island allows methyl-CpG-binding proteins to bind and recruit other chromatin silencing proteins such as histone deacetylases HDACs.
DNA methylation used to be considered stable but the recent identification of ten-eleven translocation TET family proteins as methylated CpG conversion enzymes has required re-evaluation of this concept, leading to the current view that DNA methylation is more dynamic [ ]. These results highlight the importance of epigenetic DNA methylation for understanding cancerous changes in N -glycan branching. Histone tails are usually subjected to various forms of modifications e. These histone modifications are now considered to be pivotal for the epigenetic regulation of gene transcription [ ].
The mechanisms by which the N -glycan branching genes are regulated by histone modifications in cancer cells are less understood than other epigenetic mechanisms [ ]. Histones around Mgat5b transcription start sites are modified in a neural-cell-specific manner, which is subsequently required for the efficient binding of the specific transcription activators NeuroD1 and CTCF [ 64 , 65 ]. In future studies, it would be interesting to investigate the as-yet-unknown mechanisms involving histone modifications for the other N -glycan branching genes in cancer cells.
An increasing number of reports on miRNA-dependent mechanisms of glycan expression have been published. As expected by their abundance over 1, miRNAs have been identified in humans , many glyco-genes are also direct and indirect targets of miRNAs.
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In addition, the miRNAmediated suppression of FUT8 inhibited the proliferation and invasion of colorectal cancer cells. Nucleotide sugars e. Because this pathway integrates the metabolism of glucose, glutamine, acetyl-CoA and UTP [ ], cellular nutrient conditions are assumed to have a major impact on it. In addition, importantly, it is well known that sugar and energy metabolism is often altered in cancer cells compared with that in normal cells [ ].
We previously developed methods for the simultaneous quantification of various nucleotide sugars by using ion-pair reverse-phase HPLC and found significant differences in the levels of nucleotide sugars between breast and pancreatic cancer cells [ ]. Our mass isotopomer analysis further supported the notion that UDP-GlcNAc metabolism is regulated in a cell-type-specific manner [ ]. These techniques are helpful to further understand how nucleotide sugar metabolism is involved in cancerous changes in N -glycan branching.
We also identified a unique regulatory mechanism of nucleotide sugars involving a phosphodiesterase. Furthermore, knockdown of ENPP3 resulted in a change in the global cellular glycan profile, suggesting that ENPP3 globally regulates cellular glycosylation.
Similar mechanisms probably regulate nucleotide sugars in normal and cancer cells, leading to indirect regulation of the cellular glycosylation system. The N -glycan branching enzymes are considered to be localized in the Golgi apparatus like many other glycosyltransferases. Although no reports have yet been published showing that their subcellular localization is altered in cancer cells, cancer-specific changes in the localization of glycosyltransferases have been shown to have a significant impact on the cellular glycosylation system [ , ].
Notably, our group reported that caveolin-1 appeared to regulate the localization and cellular activity of GnT-III in hepatoma cells [ ], leading to the possibility of bisecting GlcNAc being involved in caveolinrelated cancer phenotypes [ ]. Recently, a Golgi-resident protease, SPPL3, was found to be responsible for the physiological shedding of various glycosyltransferases including GnT-V [ 50 , 51 ].
The overexpression of SPPL3 was found to suppress cellular glycosylation, especially the late-stage maturation of N -glycosylation and SPPL3-deficient cells conversely showed phenotypes of hyper-glycosylation.
Although the consequences of shedding of other glycosyltransferases by SPPL3 are still unclear, it is strongly expected that SPPL3 down regulates multiple enzymes involved in the cellular glycosylation system. It would also be interesting to determine the relationships between the SPPL3-mediated shedding of N -glycan branching enzymes and cancer biology in future studies.
The multiple mechanisms regulating N -glycan branching in cancer cells described here are summarized in Figure 4 and the references for the upregulation of the N -glycan branching enzymes in various cancer types are listed in Table 1. Notably, other mechanisms are also involved in regulation of N -glycan branching such as trafficking rate of acceptor proteins, regulation of nucleotide sugar transporters, solvent accessibility at the sites to be modified [ ] and crosstalk to other posttranslational modifications.
Table of contents
In fact, multiple N -glycan changes were observed in colorectal cancer in a stage-specific manner and N -glycan branching was found to also be regulated by cellular EGFR-status [ ]. Multiple factors should be considered for better understanding how N -glycan branching is dysregulated in cancer. As described above, the changes in N -glycan branching are expected to be good targets for cancer therapy, including as biomarkers for early detection and anticancer drugs. To develop glyco-related biomarkers, antibodies or lectins are currently used for glycan detection. Unfortunately however, the low antigenicity of glycans and the low affinities of lectins often make it difficult to detect target glycans with high sensitivity and specificity.
Technical advances will be needed to detect target glycans for clinical applications. Glycomic and glycoproteomic techniques using mass-spectrometry have been greatly improved [ , ]. Furthermore, a click chemistry approach using a sugar analog is one unique and promising strategy for this [ , ]. This approach can specifically label and tag target sugars in cells by using alkynyl- or azide-sugars as bioorthogonal chemical reporters.
Although this metabolic approach is highly specific and is very promising for the selective detection of a target sugar, there are still some shortcomings of using non-natural sugars, such as cytotoxicity and low efficiency of labeling [ ].
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In addition, because a sugar analog is broadly incorporated into various types of glycan, we are currently unable to label a specific branch or specific part of glycans. The development of a new type of sugar analog is thus required to apply this click strategy to clinical research, such as for biomarker discovery.
Chemical inhibitors or activators of the N -glycan branching enzymes are considered to be useful as potential anticancer drugs, as well as tools for basic research. In particular, GnT-V inhibitors would be of great interest regarding the development of anticancer drugs. To date, no specific and potent inhibitors of these enzymes have been established, although chemically designed substrate analogs were shown to have inhibitory activities toward GnT-V or GnT-III [ , ].
The current lack of data on the tertiary structure of branching enzymes, except for Fut8 [ ], makes it difficult to design in silico chemical modulators of their activity. An effective assay system to measure their activity for high-throughput screening also remains to be established. In this review, we have provided an overview of how N -glycan branches are expressed and function in cancer cells.
We know that the synthesis of N -glycan branches in cancer cells is regulated by multiple mechanisms encompassing genetics, epigenetics, the localization and shedding of the branching enzymes and the levels of donor substrates. Although our knowledge on this field has been increasing, there are still obstacles to its clinical application.