Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target

Abstract

Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target. USP18 is the major DUB that removes IFN-stimulated gene 15 (ISG15) from conjugated proteins. Prior work discovered that engineered loss of USP18 increases ISGylation and in contrast to its gain decreases cancer growth by destabilizing growth-regulatory proteins. Loss of USP18 reduced cancer cell growth by triggering apoptosis. Genetic loss of USP18 repressed cancer formation in engineered murine lung cancer models. The translational relevance of USP18 was confirmed by finding its expression was deregulated in malignant versus normal tissues. Notably, the recent elucidation of the USP18 crystal structure offers a framework for developing an inhibitor to this DUB. This review summarizes strong evidence for USP18 as a previously unrecognized pharmacologic target in oncology. Cancer Res; 78(3); 587-92. ©2018 AACR.

Figure 1.

USP18 is an antineoplastic target. A. USP18 activity once inhibited will increase ISGylation and decrease stability of critical growth-regulatory proteins that are destabilized by ISGylation. B. USP18 protein levels are elevated in most examined cancers (adapted from reference 13) when compared to histopathologically normal tissues (other than for prostate cancer where variable USP18 expression was detected). Reduced USP18 protein expression profiles were observed in kidney and stomach cancers as compared to corresponding histopathologically normal tissues. C. USP18 mRNA levels are significantly elevated in diverse cancers, as indicated by analysis of The Cancer Genome Atlas (**P < 0.01, ***P < 0.001, two-tailed t tests).