The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells
The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/β-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/β-catenin pathway,...
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Veröffentlicht in: | Molecular cancer research 2015-05, Vol.13 (5), p.902-912 |
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Zusammenfassung: | The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/β-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/β-catenin pathway, to enhance the activity of the β-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/β-catenin signaling. WWOX does not affect the BCL9-2-β-catenin association and colocalizes with BCL9-2 and β-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the β-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 β-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the β-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.
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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ISSN: | 1541-7786 1557-3125 |
DOI: | 10.1158/1541-7786.MCR-14-0180 |