ISG15: An interferon-stimulated gene with critical functional implications in cancer

The interferon-stimulated gene 15 (ISG15) is induced by interferons (types I and II) in several cancer cell types. ISG15 encodes an ubiquitinlike protein that can covalently bind to target proteins via a catalytic system (known as the ISGylation system) of three enzymes similar to those in ubiquitination. The covalent conjugation of ISG15 to target proteins via ISGylation is a post-translational modification. Additionally, free ISG15 is the non-conjugated ISG15 with intracellular and extracellular distribution. The deregulation of ISG15 expression, and the two forms of ISG15 (free and conjugated) have been implicated in the development of different cancer types. Intriguingly, ISG15 has a dual role in cancer-it can act either as a pro- or an anti-tumor factor. The induction of ISG15 expression by interferons can be central to cancer progression and treatment response. Herein, we discuss findings related to ISG15 and protein ISGylation, and their association with interferon signaling in cancer. ISG15 has emerged as a critical factor in cancer development. The knowledge of ISG15 may be useful in cancer treatment.