Proteasome-associated deubiquitinases and cancer

Abstract

Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.

Keywords: Cancer; Deubiquitinases; Proteasome; Ubiquitin.

Fig. 1

Schematic representation of the UPS. Substrate protein is tagged with ubiquitin by E1, E2, and E3. Ubiquitin-tagged proteins are recognized and degraded by the proteasome

Fig. 2

Mechanisms of how proteasome inhibition inhibits cancer cell survival. a Generation of misfolded proteins due to elevated protein synthesis in cancer cells requires the UPS for detoxification. Proteasome inhibition leads to accumulation of misfolded proteins, causing proteotoxic and oxidative stress. b Proteasome inhibition leads to abrogation of NFκB pro-survival signaling

Fig. 3

Summary of DUB inhibitors and their effect. a b-AP15 and WP1130 inhibit proteasomal DUBs, preventing deubiquitination at the proteasome. Blocking of deubiquitination prevents the proteasome from processing ubiquitin-tagged proteins. b P5091 inhibits USP7. Inhibition of USP7 prevents deubiquitination of HDM2, destabilizing it, which in turns stabilizes p53. p53 activates pro-apoptotic pathways, causing tumor cell death. c USP8i inhibits USP8. USP8 mediates the recycling of RTKs from the cell surface. Inhibition by USP8i may reduce surface expressed levels of RTKs, providing an alternative avenue of inhibiting oncogenic RTK signaling in EGFR inhibitor-resistant tumors