Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Mar;240(3):296-304.
doi: 10.1177/1535370214561590. Epub 2014 Dec 22.

WWOX: a fragile tumor suppressor

Morgan S Schrock  1 , Kay Huebner  2
Affiliations
Review

WWOX: a fragile tumor suppressor

Morgan S Schrock et al. Exp Biol Med (Maywood). 2015 Mar.

Abstract

WWOX, the WW domain-containing oxidoreductase gene at chromosome region 16q23.3-q24.1, spanning chromosomal fragile site FRA16D, encodes the 46 kDa Wwox protein, a tumor suppressor that is lost or reduced in expression in a wide variety of cancers, including breast, prostate, ovarian, and lung. The function of Wwox as a tumor suppressor implies that it serves a function in the prevention of carcinogenesis. Indeed, in vitro studies show that Wwox protein interacts with many binding partners to regulate cellular apoptosis, proliferation, and/or maturation. It has been reported that newborn Wwox knockout mice exhibit nascent osteosarcomas while Wwox(+/-) mice exhibit increased incidence of spontaneous and induced tumors. Furthermore, absence or reduction of Wwox expression in mouse xenograft models results in increased tumorigenesis, which can be rescued by Wwox re-expression, though there is not universal agreement among investigators regarding the role of Wwox loss in these experimental models. Despite this proposed tumor suppressor function, the overlap of the human WWOX locus with FRA16D sensitizes the gene to protein-inactivating deletions caused by replication stress. The high frequency of deletions within the WWOX locus in cancers of various types, without the hallmark protein inactivation-associated mutations of "classical" tumor suppressors, has led to the proposal that WWOX deletions in cancers are passenger events that occur in early cancer progenitor cells due to fragility of the genetic locus, rather than driver events which provide the cancer cell a selective advantage. Recently, a proposed epigenetic cause of chromosomal fragility has suggested a novel mechanism for early fragile site instability and has implications regarding the involvement of tumor suppressor genes at chromosomal fragile sites in cancer. In this review, we provide an overview of the evidence for WWOX as a tumor suppressor gene and put this into the context of fragility associated with the FRA16D locus.

Keywords: FOR gene; FRA16D; WOX1; WWOX-human gene; Wwox- human/mouse protein; Wwox- mouse gene; fragile sites.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chromosome fragility and genetic alterations at the WWOX/FRA16D locus. (a) Metaphase spread showing G-banded metaphase chromosomes and homozygous breaks at 16q23, with corresponding chromosome 16 ideogram, identifying the colocalization of WWOX and FRA16D. (b) Schematic of the WWOX gene showing exons as white boxes below their corresponding genomic location. Genetic alterations are listed in blue (homozygous) or orange (heterozygous) with deletions denoted as gaps. Samples shown for homozygous deletions are epithelial cancer cell lines: PEO1/4/6 cell lines derived from ovarian adenocarcinoma, SCLC derived from small cell lung carcinoma including the cell lines WX330 and NCI-H69, PANC1 cell line derived from pancreatic ductal adenocarcinoma, HCT116 cell line derived from colorectal carcinoma, AGS cell line derived from stomach adenocarcinoma, CO-115 and KM12C cell lines were derived from colon carcinomas. Heterozygous deletions were detected in breast and prostate cancers via PCR microsatellite analysis. (c) Replication-sequencing data generated from ENCODE for the WWOX locus in epithelial cells. Cell cycle phases are indicated on the left with S phase subdivided into four fractions. The WWOX locus relies on long-traveling forks (gray arrows) emanating from replication origins (orange circles) located in the flanking regions to converge in G2 phase, resulting in late completion of replication for the center of the gene. (A color version of this figure is available in the online journal.)
Figure 2
Figure 2
WWOX/Wwox expression alterations in human cancers. Summary of reports showing correlations between reduced/absent WWOX/Wwox expression, LOH (loss of heterozygosity), or normal WWOX expression in various common human cancers. (A color version of this figure is available in the online journal.)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bednarek AJ, Laflin KJ, Daniel RL, Liao Q, Hawkins KA, Aldaz CM. WWOX, a novel WW domain-containing protein mapping to human chromosome 16q23.3–16q24.1, a region frequently affected in breast cancer. Cancer Res 2000; 60: 2140–5. - PubMed
    1. Ludes-Meyers JH, Bednarek AK, Popescu NC, Bedford M, Aldaz CM. WWOX, the common chromosomal fragile site, FRA16D, cancer gene. Cytogenet Genome Res 2003; 100: 101–10. - PMC - PubMed
    1. Sudol M, Recinos CC, Abraczinskas J, Humbert J, Farooq A. WW or WoW: the WW domains in a union of bliss. IUBMB 2005; 57: 773–8. - PubMed
    1. McDonald CB, Buffa L, Bar-Mag T, Salah Z, Bhat V, Mikles DC, Deegan BJ, Seldeen KL, Malhotra A, Sudol M, Aqeilan RI, Nawaz Z, Farooq A. Biophysical basis of the binding WWOX tumor suppressor to WBP1 and WBP2 adaptors. J Mol Biol 2012; 422: 58–74. - PMC - PubMed
    1. Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM. WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function. Cancer Res 2005; 15: 6764–71. - PubMed

Publication types

LinkOut - more resources