Deubiquitinases in cancer: new functions and therapeutic options

Abstract

Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

The functional and pathologic relevance of autophagy proteases

“…35 and Figure 1). This additional role of Atg4 has been described as an important process for the dynamism of autophagy, as it provides a new source of active Atg8 to maintain a deubiquitinating enzymes (DUBs) (21), also contributes to selective autophagy of proteins and organelles (22)(23)(24)(25). In fact, DUBs have been shown to control selective autophagy levels in basal conditions (26)(27)(28), and their activity could be crucial in different pathologies such as Parkinson's disease and pathogen infections associated with autophagy dysfunction (29,30).…”

Deubiquitinase FAM/USP9X Interacts with the E3 Ubiquitin Ligase SMURF1 Protein and Protects It from Ligase Activity-dependent Self-degradation

“…A group of ubiquitin-specific proteases, de-ubiquitinating enzymes (DUBs), can cleave ubiquitin from its substrates (27). Most DUBs carry out this activity through a highly conserved cysteine in the catalytic domain (28). The major consequence of DUB-initiated deubiquitination includes ubiquitin biogenesis/recycling, substrate stabilization, and cell signaling modulation through ubiquitin-chain editing (29,30).…”

The role of K63‐linked polyubiquitination in cardiac hypertrophy

“…The mammalian genome encodes nearly 100 putative DUBs. DUBs are classified into 6 subfamilies according to the structure of their catalytic domain: Ub‐specific proteases (USPs), Ub C‐terminal hydrolases (UCHs), ovarian tumour‐like proteases (OTUs), JAB1/MPN/Mov34 metalloenzymes (JAMMs), Machado‐Jakob disease (MJD) proteases and a recently identified monocyte chemotactic protein‐induced protein (MCPIP) family 16, 26, 27, 28. This family of DUBs is activated depending on their specificity for the type of Ub chain conjugation attached to the substrate 28.…”