Expression, regulation and function of the ISGylation system in prostate cancer

Abstract

The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, ARdependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR þ androgensensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

The ubiquitin-like molecule interferon-stimulated gene 15 is overexpressed in human prostate cancer

“…Futhermore, increased expression of ISG15 and ISGylated protein have been shown in human cancer cell lines (19). In addition, in the current study, it was reported that the ISGylation system controled AR mRNA and protein expression and AR played a crucial role in the modulation of prostate cell proliferation and was involved in the development and progression of prostate cancer (20). In our study, we also showed a positive association between the expression of ISG15 and PC cell growth or survival.…”

Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

“…In vitro cell line-based studies have revealed contrary roles for protein ISGylation in tumorigenesis (27)(28)(29). However, these conclusions depend largely on cell-autonomous events, such as cell proliferation, cell death, and cell evasion.…”

“…Protein ISGylation is strongly enhanced upon pathogen infection and cellular stress related o IFN induction (25). Several in vitro studies using cell lines and human cancer samples have begun to reveal anti-and protumorigenic roles of ISGylation (27)(28)(29). However, in vivo studies of protein ISGylation in tumorigenesis are relatively rare and have become a pressing need for understanding the role of ISG15 in malignant progression.…”

ISG15 Is a Critical Microenvironmental Factor for Pancreatic Cancer Stem Cells

“…For example, while some reports suggest that like ubiquitylation, ISGylation may function in protein turnover (18), it may also play a previously unrecognized role in protein stability (17). The latter has been explored in systems of bladder, oral, prostate, and breast cancers, where high levels of ISG15 and its conjugates have been detected, suggesting a link between ISG15 and tumorigenesis (19)(20)(21)(22)(23)(24). For example, Kiessling and colleagues have shown that in prostate cancer, overexpression of UbE1L increased androgen receptor levels in an ISG15-dependent manner, implying that ISGylation promotes androgen receptor overexpression in cancer cells.…”