Deubiquitinating enzymes as novel anticancer targets

Abstract

Tagging proteins with mono- or poly-ubiquitin is now recognized as a multifaceted and universal means of regulating cell growth and physiology. It does so by controlling the cellular lifetime of nearly all eukaryotic proteins and the cellular localization of many critical proteins. Enzymes of the ubiquitin pathway add (ligases) or remove (deubiquitinases [DUBs]) ubiquitin tags to or from their target proteins in a selective fashion. Similarly to the kinases and their corresponding phosphatases, ubiquitin ligases and DUBs have become actively studied molecular oncology targets for drug discovery. Approximately 79 functional DUBs exist in the human proteome, suggesting that selective intervention is a reasonable therapeutic objective, with the goal of downregulating or ablating oncogene products or, alternatively, upregulating or sparing tumor suppressors. In the following review, this fascinating class of regulatory enzymes will be described, and specific examples of DUBs that are viable targets for anticancer therapy will be considered.

Figure 1. Ubiquitin pathway showing ubiquitin conjugation (E1, E2 and E3) and DUB activities

In some cases, ubiquitin chain assembly factor (E4) has been shown to enhance the conjugation of ub to certain substrates (not shown). AMP: Adenosine monophosphate; DUB: Deubiquitinase; PPi: Phosphate; ub: Ubiquitin.

Figure 2. USP7 preferentially deubiquitinates Hdm2

Relative to p53, USP7 has a higher affinity for Hdm2, thus USP7 preferentially deubiquitinates Hdm2, preventing Hdm2 from inducing its own degradation due to autoubiquitination. Subsequently, Hdm2 ubiquitinates p53, which is degraded by the proteasome. An inhibitor of USP7 is predicted to promote the degradation of Hdm2 and therefore abrogate the degradation of p53 by the ubiquitin proteosome system. ub: Ubiquitin; USP: Ubiquitin-specific protease.

Figure 3. Model for inhibition of USP2a

An inhibitor of USP2a is predicted to promote the degradation of FAS, thus abrogating the antiapoptotic activity of FAS. FAS: Fatty acid synthase; ub: Ubiquitin; USP: Ubiquitin-specific protease.