Emerging Role of Ubiquitin-Specific Protease 19 in Oncogenesis and Cancer Development

Abstract

Ubiquitination and ubiquitin-like post-translational modifications control the activity and stability of different tumor suppressors and oncoproteins. Hence, regulation of this enzymatic cascade offers an appealing scenario for novel antineoplastic targets discovery. Among the different families of enzymes that participate in the conjugation of Ubiquitin, deubiquitinating enzymes (DUBs), responsible for removing ubiquitin or ubiquitin-like peptides from substrate proteins, have attracted increasing attention. In this regard, increasing evidence is accumulating suggesting that the modulation of the catalytic activity of DUBs represents an attractive point of therapeutic intervention in cancer treatment. In particular, different lines of research indicate that USP19, a member of the DUBs, plays a role in the control of tumorigenesis and cancer dissemination. This review aims at summarizing the current knowledge of USP19 wide association with the control of several cellular processes in different neoplasms, which highlights the emerging role of USP19 as a previously unrecognized prognosis factor that possesses both positive and negative regulation activities in tumor biology. These observations indicate that USP19 might represent a novel putative pharmacologic target in oncology and underscores the potential of identifying specific modulators to test in clinical settings.

Keywords: DUBs; PTMs; USP19; metastasis; tumorigenesis; ubiquitination.

FIGURE 1

Ubiquitination pathway. The ubiquitin molecule is activated by an E1 ubiquitin activating enzyme, in an ATP-dependent step, and a thioester intermediate is formed (E1-S-ubiquitin). The ubiquitin molecule is then transferred to an E2 conjugating enzyme (E2-S-ubiquitin), and then to the final substrate by an E3 ligase. Ubiquitin bound as monomers or polymers with different topologies are associated with different biological outputs, such as regulation of enzymatic activity, localization, protein-protein interactions, among others. Sequential ubiquitin conjugations form a polyubiquitin chain on the substrate, which can be recognized and degraded by the 26S proteasome. The deubiquitinating enzymes (DUBs) are responsible for the ubiquitin molecules recycling and chain editing.

FIGURE 2

Domain architecture of USP19. It contains two CHORD-SGT1 domains (namely CS1 and CS2) at its N-terminus and a large USP domain with a ubiquitin-like domain (UBL) and myeloid translocation protein 8, Nervy protein, Deaf-1 zinc finger (MYND Zn-finger). The positions of the amino acids Cys, His, and Asp in the catalytic triad are indicated in red. There are multiple USP19 isoforms generated by alternative splicing. In particular, alternative splicing of the last exon generates isoforms with a cytoplasmic localization or isoforms anchored to the endoplasmic reticulum. This schematic depicts: (A) the USP19 isoform that contains a transmembrane (TM) domain which anchors USP19 to the endoplasmic reticulum. (B) The soluble USP19 isoform has a relatively hydrophilic region and an EEVD motif in the C-terminus instead.