Roles of F-box proteins in cancer

Abstract

F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.

Figure 1. Illustration of functional domains in the highlighted F-Box proteins, grouped by their potential functions in cancer that have been shown by available mouse models

On the basis of data from mouse genetics, pathological profiles and biochemical substrates identified for each F-box protein we group F-box proteins into four categories to indicate their roles in tumorigenesis: tumour suppressor (part a), oncogene (part b), context-dependent (part c) and undetermined (part d). β-TRCP, β-transducin repeat-containing protein; BH, β-helix; F, F-box motif; FBXL, F-box and leucine-rich repeat protein; FBXO, F-box only; FBXW, F-box/WD repeat-containing protein; HT, hemerythrin domain; IBR, in between ring fingers domain; L, leucine-rich repeat; Nop14, NOP14-like family domain; NosD, periplasmic copper-binding protein; PI31-prot-N, PI31 proteasome regulator amino-terminal domain; SKP2, S-phase kinase-associated protein 2; SPRY, SPLA and the ryanodine receptor domain; T, transmembrane region; Tr, D domain of β-TRCP; TRP, tetratricopeptide repeat; UH, UvrD/REP helicase N-terminal domain; UvrD, UvrD-like helicase C-terminal domain; W, WD40 repeat; Zu, putative zinc finger in N-recognin.

Figure 2. Different strategies for targeted therapy that aims to inhibit F-box E3 ligases on the basis of their roles in tumorigenesis

a | As indicated, for oncogenic F-box proteins, inhibitors that directly block SKP1–cullin 1–F-box protein (SCF) E3 complex formation or inhibit E3 interaction with substrates could be used as anticancer drugs. To this end, Compound #25 (also known as SZL-P1-41) has been characterized to impair the incorporation of S-phase kinase-associated protein 2 (SKP2) into a functional SCF complex, thereby terminating the oncogenic activity of SKP2. Similarly, ‘skpins’ and SKP2 E3 ligase inhibitors (SKP2E3LIs) were identified to specifically disrupt the interaction of SKP2 with p27, thereby leading to the accumulation of p27 and subsequent cell cycle arrest. b | For tumour-suppressive F-box proteins such as F-box/WD repeat-containing protein 7 (FBXW7), as genetic ablation or depletion of FBXW7 was frequently observed in cancer patients, a rational targeting of its downstream oncogenic pathway (or pathways) could be used as an efficient anticancer approach. c | For F-box proteins with context-dependent or undetermined roles in cancer, such as β-transducin repeat-containing protein 1 (β-TRCP1), disease-specific analysis would be necessary to further guide the design of personalized therapies. CDC25A, cell division cycle 25 homologue A; DEPTOR, DEP domain-containing mTOR-interacting protein; FBXO5, F-box only 5; FOXO1, forkhead box protein O1; IκB, inhibitor of nuclear factor-κB; MCL1, myeloid cell leukaemia 1; P, phosphorylation; PDCD4, programmed cell death protein 4.