Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Bouteille, Nadège Karine; Driouch, Keltouma; Hage, Perla El; Sin, Soraya; Formstecher, Étienne; Camonis, Jacques; Lidereau, Rosette; Lallemand, François

doi:10.1038/onc.2009.120

Cited by 97 publications

(114 citation statements)

References 57 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…GFP-WWOX, myc-WWOX, myc-WWOXY33R, 3xflag-Dvl-2, b-cateninDGSK, Flag-HDAC1, and Flag-HDAC3 expression vectors have already been described (7,(20)(21)(22)(23). 3xflag-BCL9-2, 3xflag-Tcf1, HA-b-catenin, HA-Pygopus-2, HA-HDAC3, and HDA-C3Y298F expression vectors were constructed by inserting the appropriate cDNAs into p3xflag-CMV-7.1 (Sigma) or phCMV2 (Gene Therapy Systems) vectors.…”

Section: Plasmidsmentioning

confidence: 99%

“…The methods have been described in detail elsewhere (7). In this study, we transfected cells seeded at a density of 80 Â 10 3 in 24-well plates.…”

Section: Luciferase Assaysmentioning

confidence: 99%

“…The methods have been described in detail elsewhere (7). Aliquots containing identical b-galactosidase activites were used for each coimmunoprecipitation experiment.…”

Section: Coimmunoprecipitation and Western Blottingmentioning

confidence: 99%

“…As bait, we used FORIII (a WWOX isoform, possessing the WW domains and a truncated SDR domain; ref. 7) and WWOX WT to screen at saturation a highly complex human placenta library. One clone corresponding to amino acids 456-714 of the cofactor of the Wnt/b-catenin pathway BCL9-2 was found to interact with both baits.…”

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

confidence: 99%

“…Recently, we have defined WWOX as a novel negative regulator of the Wnt/b-catenin pathway in different human breast cancer cell lines, acting, at least in part, by sequestrating dishevelled-2 protein (Dvl-2) in the cytoplasm (7). This signaling pathway modulates multiple developmental processes and controls homeostatic self-renewal in a number of adult tissues; its aberrant activation plays an important role in the development of many human cancer types such as colon and breast cancers (8,9).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Plasmidsmentioning

confidence: 99%

“…The methods have been described in detail elsewhere (7). In this study, we transfected cells seeded at a density of 80 Â 10 3 in 24-well plates.…”

Section: Luciferase Assaysmentioning

confidence: 99%

“…The methods have been described in detail elsewhere (7). Aliquots containing identical b-galactosidase activites were used for each coimmunoprecipitation experiment.…”

Section: Coimmunoprecipitation and Western Blottingmentioning

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

WWOX: Its genomics, partners, and functions

Mare¹,

Salah²,

Aqeilan³

2009

J of Cellular Biochemistry

130

156

View full text Add to dashboard Cite

The WW domain-containing oxidoreductase (WWOX) spans one of the most active common fragile sites (CFSs) involved in cancer, FRA16D. WWOX encodes a 46-kDa protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase (SDR) domain. Through its WW domain, Wwox interacts with its partners and modulates their functions. Our data indicate that Wwox suppresses the transactivation function of several transcription factors implied in neoplasia by sequestering them in the cytoplasm. Work from our laboratory and other research groups have demonstrated that Wwox participates in a number of cellular processes including growth, differentiation, apoptosis, and tumor suppression. Targeted deletion of the Wwox gene in mice causes increased spontaneous and chemically induced tumor incidence supporting bona fide tumor suppressor function of WWOX. Moreover, generation of the Wwox-deficient mice uncovers, at least in part, some of the physiological in vivo functions of the WWOX gene. This review focuses on recent progress that elucidates Wwox functions in biology and pathology.

show abstract

Epigenetic Pathways and Glioblastoma Treatment: Insights From Signaling Cascades

Allen

Stathias

Maloof

et al. 2015

J of Cellular Biochemistry

View full text Add to dashboard Cite

There is an urgent need to identify novel therapies for glioblastoma (GBM) as most therapies are ineffective. A first step in this process is to identify and validate targets for therapeutic intervention. Epigenetic modulators have emerged as attractive drug targets in several cancers including GBM. These epigenetic regulators affect gene expression without changing the DNA sequence. Recent studies suggest that epigenetic regulators interact with drivers of GBM cell and stem-like cell proliferation. These drivers include components of the Notch, Hedgehog, and Wingless (WNT) pathways. We highlight recent studies connecting epigenetic and signaling pathways in GBM. We also review systems and big data approaches for identifying patient specific therapies in GBM. Collectively, these studies will identify drug combinations that may be effective in GBM and other cancers.

show abstract

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Cited by 97 publications

References 57 publications

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

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

WWOX: Its genomics, partners, and functions

Epigenetic Pathways and Glioblastoma Treatment: Insights From Signaling Cascades

Contact Info

Product

Resources

About