Targeting the untargetable: RB1-deficient tumours are vulnerable to Skp2 ubiquitin ligase inhibition

• Published in: British journal of cancer Vol. 127; no. 6; pp. 969 - 975
• Main Authors: Gupta, Pranav, Zhao, Hongling, Hoang, Bang, Schwartz, Edward L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-10-2022; Nature Publishing Group
• Subjects: 631/154/555; 631/67/1059/602; Apoptosis; Binding sites; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; CDC2-CDC28 Kinases - genetics; CDC2-CDC28 Kinases - metabolism; Cell cycle; Cell differentiation; Cell proliferation; Cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclin-dependent kinases; Drug Resistance; Enzymatic activity; Enzyme inhibitors; Epidemiology; Gene expression; Humans; Kinases; Metastases; Molecular Medicine; Mutation; Neoplasms - genetics; Oncology; Perspective; Proteasomes; Proteins; Retinoblastoma; Retinoblastoma Binding Proteins - metabolism; Retinoblastoma Protein; S phase; S-Phase Kinase-Associated Proteins - genetics; S-Phase Kinase-Associated Proteins - metabolism; Skp2 protein; Therapeutic targets; Tumor suppressor genes; Tumors; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-01898-0

Proteins that regulate the cell cycle are accumulated and degraded in a coordinated manner during the transition from one cell cycle phase to the next. The rapid loss of a critical protein, for example, to allow the cell to move from G1/G0 to S phase, is often regulated by its ubiquitination and subsequent proteasomal degradation. Protein ubiquitination is mediated by a series of three ligases, of which the E3 ligases provide the specificity for a particular protein substrate. One such E3 ligase is SCF
Skp1/Cks1
, which has a substrate recruiting subunit called S-phase kinase-associated protein 2 (Skp2). Skp2 regulates cell proliferation, apoptosis, and differentiation, can act as an oncogene, and is overexpressed in human cancer. A primary target of Skp2 is the cyclin-dependent kinase inhibitor p27 (CDKN1b) that regulates the cell cycle at several points. The RB1 tumour suppressor gene regulates Skp2 activity by two mechanisms: by controlling its mRNA expression, and by an effect on Skp2’s enzymatic activity. For the latter, the RB1 protein (pRb) directly binds to the substrate-binding site on Skp2, preventing protein substrates from being ubiquitinated and degraded. Inactivating mutations in RB1 are common in human cancer, becoming more frequent in aggressive, metastatic, and drug-resistant tumours. Hence, RB1 mutation leads to the loss of pRb, an unrestrained increase in Skp2 activity, the unregulated decrease in p27, and the loss of cell cycle control. Because RB1 mutations lead to the loss of a functional protein, its direct targeting is not possible. This perspective will discuss evidence validating Skp2 as a therapeutic target in RB1-deficient cancer.