TY - JOUR
T1 - The tumor-suppressor WWOX and HDAC3 inhibit the transcriptional activity of the b-catenin coactivator BCL9-2 in breast cancer cells
AU - El-Hage, Perla
AU - Petitalot, Ambre
AU - Monsoro-Burq, Anne Helene
AU - Maczkowiak, Frederique
AU - Driouch, Keltouma
AU - Formstecher, Etienne
AU - Camonis, Jacques
AU - Sabbah, Michele
AU - Bieche, Ivan
AU - Lidereau, Rosette
AU - Lallemand, Francois
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84942306715
U2 - 10.1158/1541-7786.MCR-14-0180
DO - 10.1158/1541-7786.MCR-14-0180
M3 - Article
C2 - 25678599
AN - SCOPUS:84942306715
SN - 1541-7786
VL - 13
SP - 902
EP - 912
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -
