| First Author | El-Hage P | Year | 2015 |
| Journal | Mol Cancer Res | Volume | 13 |
| Issue | 5 | Pages | 902-12 |
| PubMed ID | 25678599 | Mgi Jnum | J:227365 |
| Mgi Id | MGI:5700281 | Doi | 10.1158/1541-7786.MCR-14-0180 |
| Citation | El-Hage P, et al. (2015) The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the beta-Catenin Coactivator BCL9-2 in Breast Cancer Cells. Mol Cancer Res 13(5):902-12 |
| abstractText | The WW domain containing oxidoreductase (WWOX) has recently been shown to inhibit of the Wnt/beta-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/beta-catenin pathway, to enhance the activity of the beta-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/beta-catenin signaling. WWOX does not affect the BCL9-2-beta-catenin association and colocalizes with BCL9-2 and beta-catenin in the nucleus of the MCF-7 cells. Moreover, WWOX inhibits the beta-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 beta-catenin only when BCL9-2 is in complex with HDAC3 and inhibits its transcriptional activity, in part, by inhibiting the beta-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. |
