The landscape of the ubiquitin-proteasome system in cancer

The discovery and elucidation of the ubiquitin-proteasome system (UPS [ 1 , 2 ]) spanned a long period. It started with the discovery of the enzymatic cascade of conjugation of ubiquitin (Ub) to target substrates and their subsequent degradation by the proteasome. It then moved to the development of drugs that target the system and has expanded recently by the development of targeted protein degradation (TPD [ 3 , 4 ]). All along, the UPS was found to be tightly linked to cancer pathogenesis and therapeutics. Taking a global approach as described in two research articles in this issue, González-Robles et al. describe the clinical proteogenomic landscape of the UPS in cancer [ 5 , 6 ]. Thirty-five years ago, it was shown that oncoproteins are degraded by the UPS [ 7 ]. This was followed by the understanding that “degrons”, amino acid residues/sequences present in certain proto-oncoproteins and other short-lived proteins, mediate their recognition by E3 ubiquitin ligases and are frequently mutated in cancer [ 8 , 9 ]. Subsequently, Scheffner et al. identified E6-AP as the first cancer-related E3. E6-AP catalyzes the ubiquitylation and subsequent proteasomal degradation of p53 in HPV infected cells [ 10 ]. Remarkably, this degradation is mediated by the virus-encoded E6 protein that serves as a “natural” proteolysis-targeting chimera, a PROTAC-like compound, that physically connect TP53 to E6-AP. Similarly, MDM2 was identified as the E3 ligase that regulates the steady state of TP53. However, in multiple cancers, when MDM2 is in excess, it becomes an oncoprotein by mediating the uncontrolled degradation of p53 [ 11 , 12 ].