title: The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France.
authors: Perla
authors: P
authors: El-Hage
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France.
authors: Ambre
authors: A
authors: Petitalot
authors: Institut Curie, CNRS UMR3347, INSERM U1021, Centre Universitaire, Paris, France. Université Paris Sud, Centre Universitaire, Paris, France.
authors: Anne-Hélène
authors: AH
authors: Monsoro-Burq
authors: Institut Curie, CNRS UMR3347, INSERM U1021, Centre Universitaire, Paris, France. Université Paris Sud, Centre Universitaire, Paris, France.
authors: Frédérique
authors: F
authors: Maczkowiak
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France.
authors: Keltouma
authors: K
authors: Driouch
authors: Hybrigenics, 3-5 impasse Reille, Paris, France.
authors: Etienne
authors: E
authors: Formstecher
authors: INSERM U528, Institut Curie, Paris, France.
authors: Jacques
authors: J
authors: Camonis
authors: INSERM U938, hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, France.
authors: Michèle
authors: M
authors: Sabbah
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France.
authors: Ivan
authors: I
authors: Bièche
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France.
authors: Rosette
authors: R
authors: Lidereau
authors: Institut Curie, Service de Génétique, Unité de pharmacogénomique, Paris, France. francois.lallemand@curie.fr.
authors: François
authors: F
authors: Lallemand
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D010088:Oxidoreductases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D051176:beta Catenin; D000099186:Histone Deacetylase 3; C495498:BCL9L protein, human; C486071:WWOX protein, human