Overexpression of α (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells

Prostate Cancer and Prostatic Diseases, Jan 2018

Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer.

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Overexpression of α (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells

Abstract Glycosylation is recognized as one of the most common modifications on proteins. Recent studies have shown that aberrant expression of α (1,6) fucosyltransferase (FUT8), which catalyzes the transfer of fucose from GDP-fucose to core-GlcNAc of the N-linked glycoproteins, modulates cellular behavior that could lead to the development of aggressive prostate cancer. While the relationship between the abnormal expression of FUT8 and glycoprotein fucosylation in different prostate cancer cells has been demonstrated, there is no evidence that shows dysregulated fucosylation might be involved in prostate cancer progression from androgen-dependent to castration-resistant prostate cancer. In this study, using a proteomics approach, we analyzed androgen-dependent and androgen-resistant LAPC4 cells and identified FUT8 to be significantly overexpressed in the androgen-resistant LAPC4 cells. These findings were independently confirmed in LAPC4 cells that were treated with non-steroidal anti-androgen (bicalutamide) and in the in vivo castrated tumor xenograft models. Similarly, we also demonstrated that overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. To our knowledge, this is the first study reporting the functional role of fucosylated enzyme in the development of castration-resistant prostate cancer. Introduction Prostate cancer is the most common and the second leading cause of cancer death in men in the United States [1]. Clinically, organ-confined prostate cancer is managed through surgery or localized radiation therapy; however, for some patients who recur systemically following treatment or in advanced high-risk prostate cancer patients or metastatic disease, the mainstay of treatment is androgen-deprivation therapy (ADT) [2]. However, long-term ADT leads to the emergence of resistance mechanisms and ultimately the disease progresses to a castration-resistant phenotype which is fatal [3]. This transformation from a clinically localized hormone-dependent state to the androgen-resistant phenotype may involve changes in androgen receptor (AR) and associated pathways [4, 5]. Fucosylation of glycoproteins has been shown to play pivotal roles in many aspects of biological processes such as lymphocyte homing, immune responses, fertilization, and development [6]. Moreover, aberrant fucosylation, which results from the deficiency or overexpression of fucosyltransferases (FUTs), is associated with a variety of human diseases, including cancers [7, 8]. Unlike other FUTs that are functionally redundant, the α (1,6) fucosyltransferase (FUT8) is the only enzyme responsible for the α 1,6-linked (core) fucosylation that adds fucose to the inner most GlcNAc of an N-linked glycan [9]. A growing body of evidence indicates that core fucosylation is important for regulating protein functions [10, 11]. Transgenic and knockout animal models for core fucosylation have been generated to study the physiological role of FUT8 [12, 13]. Ectopic expression of FUT8 resulted in the steatosis-like phenotype in transgenic mice [14], while on the other hand, knocking out FUT8 in mice was reported to dramatically decrease the postnatal survival and inhibition of chemical-induced hepatocellular carcinoma and tumorigenesis [1, 2]. Core fucosylation is also crucial for the ligand-binding affinity of transforming growth factor (TGF)-β1 receptor, epidermal growth factor (EGF) receptor [15], and integrin α3β1 [16]. Lack of the core fucose on these receptors leads to a marked reduction in ligand-binding ability and downstream signaling. Furthermore, an increase in core fucosylation on E-cadherin has been shown to strengthen cell–cell adhesion [17]. Overexpression of FUT8 has been observed in several malignant tumors, which is linked to the severity of these cancers [18, 19]. In papillary thyroid carcinoma, higher expression of FUT8 is linked to larger tumor volumes and lymph node metastasis [20]. Similarly, in prostate cancer, we have previously observed and reported higher FUT8 expression in aggressive tumors (Gleason 8 and above) compared to its non-aggressive Gleason 6 and lower [21]. In addition, we have also reported that overexpression of FUT8 in prostate cancer cells was correlated with increased fucosylation of glycoproteins in aggressive prostate cancer cells [22]. Here we report that FUT8 overexpression was induced in castration-resistant cells and was responsible for the lower prostate-specific antigen (PSA) production and cell survival in prostate cancer. Materials and methods Cell lines and reagents The prostate cancer LAPC4 cell lines that harbor the wild-type AR, that was regularly validated by DNA typing, were obtained from Dr. Johns Isaacs in 2016 (Johns Hopkins School of Medicine), which were cultured in Iscove’s Modified Dulbecco’s Medium (IMDM) containing 10% charcoal-stripped fetal bovine serum (cFBS) (GIBCO, Carlsbad, CA), 100 U of penicillin, and 100 µg/mL (...truncated)


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Naseruddin Höti, Shuang Yang, Yingwei Hu, Punit Shah, Michael C. Haffner, Hui Zhang. Overexpression of α (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells, Prostate Cancer and Prostatic Diseases, 2018, pp. 137-146, Issue: 21, DOI: 10.1038/s41391-017-0016-7