CREBBP/EP300 bromodomains are critical to sustain the GATA1/MYC regulatory axis in proliferation

• Main Authors: Veronica Garcia-Carpizo, Sergio Ruiz-Llorente, Jacinto Sarmentero, Osvaldo Graña-Castro, David G. Pisano, Maria J. Barrero
• Format: Article
• Language: English
• Published: BMC 2018-06-01
• Series: Epigenetics & Chromatin
• Subjects: Epigenetics; Bromodomains; Proliferation; Cancer
• Online Access: http://link.springer.com/article/10.1186/s13072-018-0197-x

Abstract Background The reported antitumor activity of the BET family bromodomain inhibitors has prompted the development of inhibitors against other bromodomains. However, the human genome encodes more than 60 different bromodomains and most of them remain unexplored. Results We report that the bromodomains of the histone acetyltransferases CREBBP/EP300 are critical to sustain the proliferation of human leukemia and lymphoma cell lines. EP300 is very abundant at super-enhancers in K562 and is coincident with sites of GATA1 and MYC occupancy. In accordance, CREBBP/EP300 bromodomain inhibitors interfere with GATA1- and MYC-driven transcription, causing the accumulation of cells in the G0/G1 phase of the cell cycle. The CREBBP/CBP30 bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, resulting in a decrease in the levels of histone acetylation at these regulatory regions and consequently reduced gene expression of critical genes controlled by these transcription factors. Conclusions Our data shows that inhibition of CREBBP/EP300 bromodomains can interfere with oncogene-driven transcriptional programs in cancer cells and consequently hold therapeutic potential.