Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

Abstract

Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs.

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc

“…DUBs can remove ubiquitin from substrates and thus stabilize target proteins, as well as regulate their subcellular localization and function [25]. Ubiquitin-specific proteases (USPs) account for the majority of DUBs and are involved in a variety of cellular processes including cell proliferation, differentiation, and metabolism [26]. Furthermore, USPs are significantly correlated with the occurrence of numerous cancers including PCa.…”

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

“…P5091, as an inhibitor of USP7, actively inhibits USP7, resulting in increased steady-state protein levels of p53 and p21. Moreover, WP1130, which is found to be a partially selective DUB inhibitor, directly inhibits DUB activity of USP9x, USP5 and USP14 [33][34][35][36][37]. Notably, several DUBs have been reported to regulate MDM2 expression or transcriptional activity [8,[29][30][31][32]38].…”

USP16 Regulates Castration-Resistant Prostate Cancer Cell Proliferation by Deubiquitinating and Stablizing c-Myc

“…DUBs can remove ubiquitin from substrates and thus stabilize target proteins, as well as regulate their subcellular localization and function. [25] Ubiquitin-speci c proteases (USPs) account for the majority of DUBs and are involved in a variety of cellular processes including cell proliferation, differentiation, and metabolism [26]. Furthermore, USPs are signi cantly correlated with the occurrence of numerous cancers including PCa.…”