Deubiquitinases and the new therapeutic opportunities offered to cancer

Abstract

Deubiquitinases (DUBs) play important roles and therefore are potential drug targets in various diseases including cancer and neurodegeneration. In this review, we recapitulate structure-function studies of the most studied DUBs including USP7, USP22, CYLD, UCHL1, BAP1, A20, as well as ataxin 3 and connect them to regulatory mechanisms and their growing protein interaction networks. We then describe DUBs that have been associated with endocrine carcinogenesis with a focus on prostate, ovarian, and thyroid cancer, pheochromocytoma, and adrenocortical carcinoma. The goal is enhancing our understanding of the connection between dysregulated DUBs and cancer to permit the design of therapeutics and to establish biomarkers that could be used in diagnosis and prognosis.

Keywords: A20; BAP1; CYLD; UCHL1; USP22; USP7; ataxin 3; deubiquitinases.

Figure 1

Enzymatic cascades resulting in the ubiquitination, deubiquitination, and 26S proteasome degradation of substrate proteins.

Figure 2

Reactions catalyzed by deubiquitinases (DUBs). (A) Mature ubiquitin is generated following DUB cleavage. (B) DUBs recycle ubiquitin on proteins destined for degradation by the 26S proteasome. (C) DUBs deubiquitinate substrate proteins. (D) DUBs regulate ubiquitin chain editing.

Figure 3

Domain architecture of selected DUBs: USP7, CYLD, USP22, A20, UCHL1, BAP1, ataxin 3, and RPN11.