Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction

Abstract

Regulation of ubiquitination is associated with multiple processes of tumorigenesis and development, including regulation of the tumor immune microenvironment. Deubiquitinating enzymes (DUBs) can remove ubiquitin chains from substrates, thereby stabilizing target proteins and altering and remodeling biological processes. During tumorigenesis, deubiquitination-altered biological processes are closely related to tumor metabolism, stemness, and the immune microenvironment. Recently, tumor microenvironment (TME) modulation strategies have attracted considerable attention in cancer immunotherapy. Targeting immunosuppressive mechanisms in the TME has revolutionized cancer therapy. Prostate cancer (PC) is one of the most common cancers and the second most common cause of cancer-related death in men worldwide. While immune checkpoint inhibition has produced meaningful therapeutic effects in many cancer types, clinical trials of anti-CTLA4 or anti-PD1 have not shown a clear advantage in PC patients. TME affects PC progression and also enables tumor cell immune evasion by activating the PD-1/PD-L1 axis. Over the past few decades, an increasing number of studies have demonstrated that deubiquitination in PC immune microenvironment may modulate the host immune system’s response to the tumor. As the largest and most diverse group of DUBs, ubiquitin-specific proteases (USPs) play an important role in regulating T cell development and function. According to current studies, USPs exhibit a high expression signature in PC and may promote tumorigenesis. Elevated expression of USPs often indicates poor tumor prognosis, suggesting that USPs are expected to develop as the markers of tumor prognosis and even potential drug targets for anti-tumor therapy. Herein, we first summarized recent advances of USPs in PC and focused on the relationship between USPs and immunity. Additionally, we clarified the resistance mechanisms of USPs to targeted drugs in PC. Finally, we reviewed the major achievement of targeting USPs in cancers.

The pro-tumorigenic cytokine IL-32 has a high turnover in multiple myeloma cells due to proteolysis regulated by oxygen-sensing cysteine dioxygenase and deubiquitinating enzymes

“…IL-32 is highly expressed by activated T cells ( 35 – 38 ). DUBs are currently exploited as therapeutic targets in different cancers ( 23 , 39 – 41 ), but they may also influence the cancer microenvironment, including T cells ( 42 ). Our data show that the use of proteasome inhibitors and DUB inhibitors affects IL-32 protein levels in T cells, which should be kept in mind when using DUB inhibitors in cancer treatments.…”

Functionalized Gold Nanoparticles Suppress the Proliferation of Human Lung Alveolar Adenocarcinoma Cells by Deubiquitinating Enzymes Inhibition

“…However, there are no reports on the effects of different functionalized AuNPs on deubiquitinating enzymes (DUBs) and their utility in understanding anticancer pathways. DUBs are an important group of enzymes that play a significant role in cancer pathogenesis, development, and proliferation by removing attached ubiquitin from the substrate. , They are classified into ubiquitin c-terminal hydrolases (UCHs), ubiquitin specific proteases (USPs), ovarian tumor proteases (OTUs), machado Joephin domain proteases (MJDs), monocyte chemotactic protein induced proteins (MCPIPs), and JAB1/MPN/Mov34 metalloenzyme (JAMM). − Among these DUBs, USPs, and UCHs are the most well-studied as they are highly overexpressed in human cancers, suggestive of their roles in tumor progression. , It has been found that cell survival in liver, breast, and colorectal cancers was promoted by an elevated level of USPs through simultaneously inhibiting apoptotic proteins and promoting tumor metastasis. , UCHL-1 overexpression has also been positively correlated with development, invasiveness, and chemotherapy resistance in some cancers including pancreatic, myeloma, neuroblastoma, nonsmall cell lung cancer (NSCLC), prostate, and lymphoma. , The overarching aim of this study is to understand the effects of tannate, citrate, and PVP functionalized 5 nm AuNPs on DUBs with a particular focus on USPs and UCHL-1 in A549 cells proliferation and toxicity. The study further hypothesized if the inhibition of these DUBs could lead to the downregulation of PI3K/AKT/mTOR, Wnt signaling pathway related proteins, and activation of mitochondrial apoptosis.…”

“…DUBs are an important group of enzymes that play a significant role in cancer pathogenesis, development, and proliferation by removing attached ubiquitin from the substrate. 17 , 18 They are classified into ubiquitin c-terminal hydrolases (UCHs), ubiquitin specific proteases (USPs), ovarian tumor proteases (OTUs), machado Joephin domain proteases (MJDs), monocyte chemotactic protein induced proteins (MCPIPs), and JAB1/MPN/Mov34 metalloenzyme (JAMM). 19 − 22 Among these DUBs, USPs, and UCHs are the most well-studied as they are highly overexpressed in human cancers, suggestive of their roles in tumor progression.…”