WW domain-containing oxidoreductase: a candidate tumor suppressor

Chang, Nan Shan; Hsu, Li Jin; Lin, Yee Shin; Lai, Feng‐Jie; Sheu, Hamm Ming

doi:10.1016/j.molmed.2006.11.006

Cited by 117 publications

(264 citation statements)

References 65 publications

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“…These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11,17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3).…”

mentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

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Genomic instability is a hallmark of cancer. The WW domaincontaining oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.genomic instability | common fragile sites | WW domain-containing oxidoreductase | ataxia telangiectasia-mutated | ITCH G enomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1-3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10-13). Ectopic expression of WWOX in WWOXnegative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10,11,14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14-16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19,20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22-24). ...

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mentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

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“…In agreement with this, WWOX contains two WW domains and both of them could bind PY motifs, the other WW domain (WW2) may contribute to the interaction with BCL9-2. Furthermore, the involvement of SDR domain of WWOX in protein-protein interaction has been shown (35). Our results indicate that PPPY motif and class 1 WW domain are critical for WWOX-BCL9-2 interaction.…”

Section: Wwox Interacts With the B-catenin Coactivator Bcl9-2mentioning

confidence: 52%

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

El-Hage

Petitalot

Monsoro-Burq

et al. 2015

Molecular Cancer Research

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The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/b-catenin pathway by preventing the nuclear import of disheveled 2 (DVL2) in human breast cancer cells. Here, it is revealed that WWOX also interacts with the BCL9-2, a cofactor of the Wnt/b-catenin pathway, to enhance the activity of the b-catenin-TCF/LEF (T-cell factor/ lymphoid enhancer factors family) transcription factor complexes. By using both a luciferase assay in MCF-7 cells and a Xenopus secondary axis induction assay, it was demonstrated that WWOX inhibits the BCL9-2 function in Wnt/b-catenin signaling. WWOX does not affect the BCL9-2-b-catenin association and colocalizes with BCL9-2 and b-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the b-catenin-TCF1 interaction. Further examination found that HDAC3 associates with BCL9-2, enhances the inhibitory effect of WWOX on BCL9-2 transcriptional activity, and promotes the WWOX-BCL9-2 interaction, independent of its deacetylase activity. However, WWOX does not influence the HDAC3-BCL9-2 interaction. Altogether, these results strongly indicate that nuclear WWOX interacts with BCL9-2 associated with b-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the b-catenin-TCF1 interaction. The promotion of the WWOX-BCL9-2 interaction by HDAC3, independent of its deacetylase activity, represents a new mechanism by which this HDAC inhibits transcription. Implications:The inhibition of the transcriptional activity of BCL9-2 by WWOX and HDAC3 constitutes a new molecular mechanism and provides new insight for a broad range of cancers.

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“…The human and mouse WWOX/Wwox gene was first isolated independently by 3 laboratories in year 2000 (Smith et al, 2007;Del Mare et al, 2009;Chang et al, 2007Chang et al, , 2010reviews). Human WWOX gene possesses approximately 1 million bases with 9 exons and codes for a 46-kDa protein containing 414 amino acids.…”

Section: Tumor Suppressor Wwox/for/wox1 -A Protein Possessing Ww and mentioning

confidence: 99%

“…When WWOX/WOX1 becomes activated by stress stimuli such as UV light and tumor necrosis factor, Tyr33 is phosphorylated in the first WW domain (Chang, 2002;Chang et al, 2003aChang et al, , 2003bChang et al, , 2005aChang et al, , 2007Lai et al, 2005;Lo et al, 2008). Tyrosine kinase Src is known to phosphorylate Tyr33 in WWOX/WOX1 (Aqeilan et al, 2004a).…”

Section: Tumor Suppressor Wwox/for/wox1 -A Protein Possessing Ww and mentioning

confidence: 99%

WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

Su¹,

Chen²,

Chen³

et al. 2012

Sex Hormones

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WW domain-containing oxidoreductase: a candidate tumor suppressor

Cited by 117 publications

References 65 publications

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

WW Domain-Containing Oxidoreductase is a Potential Receptor for Sex Steroid Hormones

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