A comprehensive analysis of FUT8 overexpressing prostate cancer cells reveals the role of EGFR in castration resistance

Naseruddin Höti, Tung Shing Lih, Jianbo Pan, Yangying Zhou, Ganglong Yang, Ashely Deng, Lijun Chen, Mingmimg Dong, Ruey Bing Yang, Cheng Fen Tu, Michael Haffner, Qing Kay Li, Hui Zhang

Research output: Contribution to journalArticle

Abstract

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.

Original languageEnglish (US)
Article number468
JournalCancers
Volume12
Issue number2
DOIs
StatePublished - Feb 2020

Keywords

  • Alpha (1,6) fucosyltransferase
  • Glycoproteomics
  • Prostate cancer
  • Proteomics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Höti, N., Lih, T. S., Pan, J., Zhou, Y., Yang, G., Deng, A., Chen, L., Dong, M., Yang, R. B., Tu, C. F., Haffner, M., Li, Q. K., & Zhang, H. (2020). A comprehensive analysis of FUT8 overexpressing prostate cancer cells reveals the role of EGFR in castration resistance. Cancers, 12(2), [468]. https://doi.org/10.3390/cancers12020468