DUBs, Hypoxia, and Cancer

Abstract

Alterations in protein ubiquitylation and hypoxia are commonly associated with cancer. Ubiquitylation is carried out by three sequentially acting ubiquitylating enzymes and can be opposed by deubiquitinases (DUBs), which have emerged as promising drug targets. Apart from protein localization and activity, ubiquitylation regulates degradation of proteins, among them hypoxia-inducible factors (HIFs). Thereby, various E3 ubiquitin ligases and DUBs regulate HIF abundance. Conversely, several E3s and DUBs are regulated by hypoxia. While hypoxia is a powerful HIF regulator, less is known about hypoxia-regulated DUBs and their impact on HIFs. Here, we review current knowledge about the relationship of E3s, DUBs, and hypoxia signaling. We also discuss the reciprocal regulation of DUBs by hypoxia and use of DUB-specific drugs in cancer. Increased Protein Turnover and Hypoxia Are Features of CancerCancer growth is associated with excessive protein synthesis and degradation. Among the pathways that regulate protein homeostasis, proteasomal protein degradation mediated by ubiquitylation (see Glossary) is gaining attention in cancer therapy because it is highly selective and, as a result, proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have been approved for mantle cell lymphoma and multiple myeloma therapy [1].In addition, cancer growth is also associated with the development of limited oxygenation (commonly called tumor hypoxia). This is often exemplified by an increased amount of proteins from the hypoxia-inducible transcription factor-a family (HIFs). Commonly, in cancers of the bladder, brain, breast, colon, esophagus, head/neck, liver, lung, pancreas, skin, stomach, and uterus, as well as in acute lymphocytic and myeloid leukemias, the appearance of HIFs is associated with a poor prognosis [2]. While hypoxia appears to be a powerful regulator of the HIF ubiquitylation process [3], much less is known about hypoxia-regulated deubiquitinases (DUBs) and the impact of DUBs on the HIF system. DUBs act as both tumor suppressors and oncogenes and have thus emerged as promising therapeutic targets in cancer. Here, we summarize the current knowledge about the reciprocal connection of DUBs with hypoxia signaling and the use of DUB-specific drugs in cancer. Protein Ubiquitylation and DUBsUbiquitylation is a process where the small molecule ubiquitin is attached to lysine (K) residues in target proteins, either as monoubiquitin or in polyubiquitin chains. This requires three different types of enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-ligases (E3). Although ubiquitylation is mainly involved in the regulation of degradation of proteins by the 26S proteasome, it also affects many other cellular processes, such as transcription and DNA repair, cell cycle control, inflammation, and apoptosis [4] (Figure 1 and Box 1).DUBs are enzymes that can reverse ubiquitylation. The human genome encodes for up to 100 DUBs, divided into seven subgroups, depending on sequence and s...

The role of ubiquitination and deubiquitination in cancer metabolism

“…In this review, we highlight the roles of ubiquitination and deubiquitination as modulators of cancer metabolism. Facing metabolic stresses, such as hypoxia, ubiquitination and deubiquitination in cancer cells can be abnormally regulated [10,270]. On the other hand, dysregulated ubiquitination and deubiquitination play nonnegligible roles in cancer metabolism by involving in the regulation of metabolic reprogramming related signaling pathways, transcription factors as well as metabolic enzymes.…”

“…Deubiquitination is catalyzed by deubiquitinating enzymes (DUBs) to remove ubiquitin from ubiquitinated proteins, thus reversing the ubiquitination process [ 7 ]. About 100 DUBs fall into seven subgroups: the ubiquitin-specific proteases (USPs), the ubiquitin C-terminal hydrolases (UCHs), the ovarian tumor proteases (OTUs), the Machado-Josephin domain proteases (MJDs), the JAB1/MPN+/MOV34 (JAMM) domain proteases, the monocyte chemotactic protein-induced proteins (MCPIPs), and the motif interacting with ubiquitin-containing DUB family (MINDY) [ 10 ]. Dynamic conversion between ubiquitination and deubiquitination is closely related to various cellular functions and thus, its dysregulation results in multiple disease, such as neurodegenerative diseases and cancer [ 38 ].…”

“…Genetic and epigenetic aberrations, such as mutation, amplification and deletion, can be the common causes of dysregulated ubiquitination and deubiquitination in cancer cells [ 9 ]. Ubiquitination and deubiquitination can also be abnormally regulated by transcriptional, translational or posttranslational mechanisms in cancer cells, exerting oncogenic or anti-cancer roles in carcinogenesis [ 7 , 8 , 10 ]. In recent years, the involvement of ubiquitination and deubiquitination in the regulation of metabolic reprogramming in cancer cells has received a growing body of attention [ 11 ].…”

Modifying the tumour microenvironment and reverting tumour cells: New strategies for treating malignant tumours

“…The hypoxic TME harbours cells with a burst of proliferation activity, effective for overgrowing a mass of tumour. 27 It has been identified a bidirectional cross-linking between hypoxia and angiogenesis so that the activity of either one potentiating another. 28,29 Tumour angiogenesis also results in low intratumoral drug concentrations and inhibits immune cell infiltration of the TME, thereby laying the foundation for drug resistance, immune escape and metastasis.…”

The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating its Localisation, Stability and Activity

“…Aside from ubiquitination, the action of deubiquitinating enzymes (termed DUBs) are well-known for their roles in regulating HIF-α. The action of DUBs on HIFs has been extensively and recently reviewed and will not be covered here [37,38].…”