Ubiquitin-Conjugating Enzymes in Cancer

Abstract

The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.

Keywords: cancer; ubiquitin-conjugating enzyme; ubiquitination.

Figure 1

Ubiquitination cycle. (1) Activation: ubiquitin (Ub) is activated by the ubiquitin-activating enzyme (E1) in an ATP-dependent manner. (2) Conjugation: the ubiquitin-conjugating enzyme (E2) transfers the activated Ub to the ubiquitin-ligase enzyme (E3). (3) Ligation: an E3 ligase recruits a target protein and is responsible for transferring the ubiquitin to the target substrate. (4) Deubiquitination: ubiquitin moieties can be removed from substrate proteins by deubiquitinase enzymes (DUB) action. Depending on the outcome of protein ubiquitination, the fates of substrates will be different. (5) Canonical K48 linkage leads to recognition by the 20S proteasome, triggering degradation of the substrate, yielding small peptide fragments and free ubiquitin. (6) Non-canonical types can be formed. Shown here is a K63 linkage, which is not recognized by the proteasome, resulting in altered function of the substrate protein, such as DNA repair, translation, and endocytosis.

Figure 2

Structural representation of E2s. Crystal structure of human UBE2A (Protein Data Bank (PDB) code 6CYO) as a representative of the UBC fold conserved among E2s. The UBC core is typically comprised of an α/β fold with four α-helices and a four-stranded β-sheet.