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Review
. 2023 May 17;12(10):1415.
doi: 10.3390/cells12101415.

The Role of FBXW7 in Gynecologic Malignancies

Riccardo Di Fiore  1   2 , Sherif Suleiman  1 , Rosa Drago-Ferrante  3 , Yashwanth Subbannayya  4 , Sarah Suleiman  5 , Mariela Vasileva-Slaveva  6   7   8 , Angel Yordanov  9 , Francesca Pentimalli  10 , Antonio Giordano  2   11 , Jean Calleja-Agius  1
Affiliations
Review

The Role of FBXW7 in Gynecologic Malignancies

Riccardo Di Fiore et al. Cells. .

Abstract

The F-Box and WD Repeat Domain Containing 7 (FBXW7) protein has been shown to regulate cellular growth and act as a tumor suppressor. This protein, also known as FBW7, hCDC4, SEL10 or hAGO, is encoded by the gene FBXW7. It is a crucial component of the Skp1-Cullin1-F-box (SCF) complex, which is a ubiquitin ligase. This complex aids in the degradation of many oncoproteins, such as cyclin E, c-JUN, c-MYC, NOTCH, and MCL1, via the ubiquitin-proteasome system (UPS). The FBXW7 gene is commonly mutated or deleted in numerous types of cancer, including gynecologic cancers (GCs). Such FBXW7 mutations are linked to a poor prognosis due to increased treatment resistance. Hence, detection of the FBXW7 mutation may possibly be an appropriate diagnostic and prognostic biomarker that plays a central role in determining suitable individualized management. Recent studies also suggest that, under specific circumstances, FBXW7 may act as an oncogene. There is mounting evidence indicating that the aberrant expression of FBXW7 is involved in the development of GCs. The aim of this review is to give an update on the role of FBXW7 as a potential biomarker and also as a therapeutic target for novel treatments, particularly in the management of GCs.

Keywords: FBXW7; LncRNAs; epigenetic; gynecologic cancers; miRNAs; mutations; target therapy; ubiquitin-proteasome system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
FBXW7 isoforms and SCF-FBXW7 complex. (A) Three FBXW7 isoforms (α, β, and γ), which are structurally different only at their N-terminal region, while sharing conserved domains in the C-terminal region. Each of these isoforms consists of three domains: dimerization domain (DD), F-box domain, and tandem WD40 repeats. (B) The SCF-FBXW7 complex in FBXW7 dimerization format for substrate ubiquitylation.
Figure 2
Figure 2
Regulation of FBXW7 showing some of the upstream regulators of FBXW7 and its downstream targets contributing to human tumorigenesis. Several proteins (p53, EBP2, Numb4, SGK1, Pin1, C/EBPδ, HES-5, Presenilin, USP28*, ERK1/2, H-Ras, PI3K, PLK1/2, and SV40 Large T), miRNAs (miR-223, miR-25, miR-27a, miR-182, miR-503, miR-129-5p, and miR-92a), and lncRNAs (MIF, MALAT1, TINCR, CASC2, and MT1JP) regulate the expression of FBXW7. FBXW7 coordinates the ubiquitin-dependent proteolysis of several key oncoproteins (AURKA, Cyclin E, c-Jun, c-Myc, c-Myb, mTOR, KLF5, Mcl-1, NFkB2 SREBP, etc.).
Figure 3
Figure 3
The frequency and distribution of FBXW7 mutation in human gynecological cancers (GC). (A) FBXW7 mutation frequency in different types of human GC, analyzed from cBioPortal Database (https://www.cbioportal.org/ (accessed on 30 November 2022)). (B) Distribution of FBXW7 mutations in the FBXW7 encoding region. The three most frequent mutation hotspots are R465C/H/L (57/270 mutations), R479Q/G/L/P (18/270 mutations), and R505C/G/H/L (35/270 mutations). Missense Mutations (n = 150) (putative driver); Missense Mutations (n = 65) (unknown significance); Truncating Mutations (n = 50) (putative driver): Nonsense, Nonstop, Frameshift deletion, Frameshift insertion, Splice site; Inframe Mutations (n = 3) (unknown significance): Inframe deletion, Inframe insertion; and Splice Mutations (n = 2) (putative driver). Both the figures are from the portal.
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Grants and funding

This paper is based upon work from COST Action CA18117—European network for Gynaecological Rare Cancer research: From Concept to Cure (GYNOCARE), supported by the European Co-operation in Science and Technology (COST). COST is a funding agency for research and innovation networks. COST actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, careers, and innovation (www.cost.eu accessed on 24 April 2023). R.D.F., S.S. (Sherif Suleiman), R.D.-F., Y.S., M.V.-S., A.Y., F.P., A.G., and J.C.-A. are action management committee members and/or form part of Working Groups 1–5, and J.C.-A. is the chairperson of this action.

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