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Acetylation inactivates the transcriptional repressor BCL6

Abstract

The proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is necessary for germinal-center formation and has been implicated in the pathogenesis of B-cell lymphomas. Here we show that the co-activator p300 binds and acetylates BCL6 in vivo and inhibits its function. Acetylation disrupts the ability of BCL6 to recruit histone deacetylases (HDACs), thereby hindering its capacity to repress transcription and to induce cell transformation. BCL6 is acetylated under physiologic conditions in normal germinal-center B cells and in germinal center–derived B-cell tumors. Treatment with specific inhibitors shows that levels of acetylation of BCL6 are controlled by both HDAC-dependent and SIR2-dependent pathways. Pharmacological inhibition of these pathways leads to the accumulation of the inactive acetylated BCL6 and to cell-cycle arrest and apoptosis in B-cell lymphoma cells. These results identify a new mechanism of regulation of the proto-oncogene BCL6 with potential for therapeutic exploitation. Furthermore, these findings provide a new mechanism by which acetylation can promote transcription not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.

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Figure 1: p300-induced acetylation of BCL6 and mapping of its acetylation sites.
Figure 2: BCL6 and p300 interact in vivo.
Figure 3: p300 inhibits the transcriptional repression function of BCL6.
Figure 4: Acetylation of BCL6 leads to its dissociation from HDACs.
Figure 5: Protein interactions and acetylation of endogenous BCL6 in B cells.
Figure 6: BCL6 expression can transform Rat-1 fibroblasts, and this ability is impaired in the BCL6-QQYQ mutant, which mimics the BCL6 acetylated state.

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Acknowledgements

We thank R. Baer and L. Pasqualucci for critical reading of the manuscript; U. Klein and G. Cattoretti for the isolation of human B cells; and J.C. Luo for the preliminary experiments on in vivo and in vitro interaction of p300 and BCL6. This work was supported by the US National Institutes of Health (to R.D.-F.).

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Correspondence to Riccardo Dalla-Favera.

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Bereshchenko, O., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet 32, 606–613 (2002). https://doi.org/10.1038/ng1018

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