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Suppression of BCL6 Function by HDAC Inhibitor Mediated Acetylation and Chromatin Modification Enhances BET Inhibitor Effects in B-cell Lymphoma Cells

Abstract: Multiple genetic aberrations in the regulation of BCL6, including in acetyltransferase genes, occur in clinically aggressive B-cell lymphomas and lead to higher expression levels and activity of this transcriptional repressor. BCL6 is, therefore, an attractive target for therapy in aggressive lymphomas. In this study romidepsin, a potent histone deacetylase inhibitor (HDACi), induced apoptosis and cell cycle arrest in Burkitt and diffuse large B-cell lymphoma cell lines, which are model cells for studying the mechanism of action of BCL6. Romidepsin caused BCL6 acetylation at early timepoints inhibiting its function, while at later timepoints BCL6 expression was reduced and target gene expression increased due to chromatin modification. MYC contributes to poor prognosis in aggressive lymphoma. MYC function is reduced by inhibition of chromatin readers of the bromodomain and extra-terminal repeat (BET) family, which includes BRD4. The novel combination of romidepsin and JQ1, a BRD4 inhibitor was investigated and showed synergy. Collectively we suggest that the combination of HDACi and BRD4i should be pursued in further pre-clinical testing.

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 Fuente: Sci Rep, 9 (1), 16495 2019 Nov 11

Editorial: Nature Publishing Group

 Año de publicación: 2019

Nº de páginas: 15

Tipo de publicación: Artículo de Revista

 DOI: 10.1038/s41598-019-52714-4

ISSN: 2045-2322

Proyecto español: SAF2014-53526-R ; SAF2017-88026-R

Url de la publicación: https://doi.org/10.1038/s41598-019-52714-4

Autores/as

MARIA GABRIELA CORTIGUERA RUIZ

WAGNER, SIMON D.

MARIA ANA BATLLE LOPEZ