Targeting Ubiquitination for Cancer Therapies

Abstract

Ubiquitination, the structured degradation and turnover of cellular proteins, is regulated by the ubiquitin-proteasome system. Most proteins that are critical for cellular regulations and functions are targets of the process. Ubiquitination is comprised of a sequence of three enzymatic steps, and aberrations in the pathway can lead to tumor development and progression as observed in many cancer types. Recent evidence indicates that targeting the ubiquitin-proteasome system is effective for certain cancer treatment, but many more potential targets might have been previously overlooked. In this review, we will discuss the current state of small molecules that target various elements of ubiquitination. Special attention will be given to novel inhibitors of E3 ubiquitin ligases, especially those in the SCF family.Ubiquitination, a step in the nonlysosomal degradation of proteins, is a crucial post-translational modification in eukaryotic organisms. Rapid and timely degradation of transcriptional regulators and other proteins by the ubiquitin-proteasome system (UPS) regulates a wide variety of cellular processes [1]. Ubiquitination involves covalent attachment of ubiquitin, a small 8-kDa protein, to a substrate and results in recognition and shuttling of the substrate to the 26S proteasome complex for degradation [2]. It is important to note that the ubiquitination process combined with the proteasome complex step is also referred to as the ubiquitin-proteasome system (UPS) or ubiquitin proteasome pathway (UPP).The ubiquitination process is tightly controlled by three families of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and finally ubiquitin-protein enzymes (E3s). There exists two E1 enzymes with ubiquitin-activating capability: UBA1 being the primary E1 and the recently discovered UBA6 with unclear functions and uncharacterized regulations [3,4]. In contrast to the small number of E1s, there are approximately 40 E2s [5,6] and 500-1000 human E3 ligases, providing both specificity and versatility [7]. The three steps of the ubiquitination process (Figure 1) have been reviewed previously [8,9]. Briefly, the activation step requires binding of both ATP and ubiquitin and links the α-carboxyl group of the C-terminal glycine residue of ubiquitin to a cysteine residue on E1, and a thioester linkage is formed between the u biquitin and E1.Then the E2 binds to both activated ubiquitin and the E1 enzyme and thus transfers the ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. Finally, the E3 catalyzes the linking of ubiquitin to a lysine residue on the substrate. Repetitions of these sequential steps results in a long chains of ubiquitin (polyubiquitin) on the protein to be degraded, and the specific lysine residue on ubiquitin used for linking (e.g., K48, K63, etc.) results in different topologies [10]. Ubiquitination was originally described as a mechanism by which cells dispose of short-lived, damaged, or abnormal proteins, but more rece...

Highly Multiplexed Quantitative Mass Spectrometry Analysis of Ubiquitylomes

“…Ubiquitylation is also a highly versatile post-translational modification, and it can involve assemblies of eight distinct chain-linkage types (M1, K6, K11, K27, K29, K33, K48, and K63), wherein K11 and K48 contribute preferentially to proteasomal turnover. In keeping with such central roles in biology, components of the UB system are frequently mutated in disease (Ciechanover and Kwon, 2015; Morrow et al, 2015). …”

Cell division cycle 34 is highly expressed in hepatitis C virus-positive hepatocellular carcinoma with favorable phenotypes

“…As UPS regulates numerous aspects of cellular function, defects in this system may result in the pathogenesis of various significant human diseases, including tumors (19,20). Ubiquitin may be added to a substrate protein by the concerted action of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3) (18).…”

“…As UPS regulates degradation of various types of protein, it is crucial in a variety of cellular processes. UPS aberrations have been observed in numerous types of human tumor (19,20). However, limited information is available regarding aberrations of CDC34 in HCC.…”

The role of K63‐linked polyubiquitination in cardiac hypertrophy

“…The proteomic studies have shown that all types of polyubiquitination co‐exist in cells 14, 15. Lys48‐linked chains are the most abundant linkage type (often > 50% of all linkages) found in cells that are primarily involved in transfer of substrate proteins to the 26S proteasome for degradation 16. However, K63‐linked polyubiquitination, the second most abundant form of ubiquitylation, has various non‐proteolytic roles in cells 8.…”

“…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.…”