BCL6 Represses Smad Signaling in Transforming Growth Factor-β Resistance

Transforming growth factor-β (TGF-β) controls a wide spectrum of cellular processes. Deregulation of TGF-β signaling contributes to the pathogenesis of many diseases including cancer and autoimmune diseases. TGF-β signaling is generally mediated through intracellular signal transducers and transcription factors called Smads. Herein, we have identified the oncoprotein BCL6 as a transcriptional corepressor of tumor suppressor Smad4. BCL6 physically interacts with Smad3 and Smad4, disrupts the Smad-p300 interaction, and represses the transcriptional activity of Smad4. In accordance, B-cell lymphoma cells with a high expression level of BCL6 were found to be refractory to TGF-β antiproliferative response, whereas knockdown of BCL6 expression in B-cell lymphoma cells partially restores the TGF-β responses. This study provides strong evidence that overexpression of BCL6 contributes to TGF-β resistance in B-cell lymphoma. [Cancer Res 2008;68(3):783–9]