Abstract A50: Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle
Authors: Francois Lamoureux, Marc Baud'huin, Lidia Rodriguez, Camille Jacques, Francoise Redini, James E. Bradner, Dominique Heymann, Benjamin Ory
Journal: Cancer Research (2014)

Abstract Osteosarcoma is the most frequent primary bone tumor that develops mainly in young adults. The survival rate at 5 years is below 30% for patients with poor response to treatment or with metastasis. The vicious cycle established between bone associated tumors and bone resorption is the central problematic of the therapeutic strategies developed for primary bone tumors or bone metastasis. The bromodomain and extra-terminal domain (BET) protein family (including BRD4) is an important class of “histone reading protein” capable to recognize the N-acetylation of lysine residues on histone tails. Bromodomains act as a scaffold for molecular complexes at the recognized histones sites in order to regulate chromatin accessibility to transcription factors and RNA polymerase. In this study we report for the first time the essential role of BRD4 in both osteoblastogenesis and osteoclastogenesis regulation. Indeed, a strong reduction of osteoblastic differentiation has been observed after BET protein inhibition associated to a transcriptional silencing of RUNX2 coincident with release of BRD4 from its locus. Moreover, we identified a BRD4-dependent RANKL activation of osteoclastogenesis on the NFATC1 promoter, leading to the inhibitory potential of JQ1 on osteoclast differentiation. Moreover the inhibition of BRD4 interferes with bone associated tumor progression through a transcriptional silencing of MYC and RUNX2 coincident with release of BRD4 from their respective locus. Indeed, in osteosarcoma tumor cell lines, BET inhibitor reduced cell growth in a dose-dependent manner and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. In vivo, BET inhibitor (IP; 50mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and HOS xenograft models compared to control. Additionnally, these results were accompanied by a decrease of associated bone lesions. Those new data support BET protein inhibition as a novel therapeutic strategy targeting simultaneously the three partners of the vicious cycle, using JQ1, a unique BET protein inhibitor. In this study, we uncover the therapeutic potential of BET bromodomain inhibition in bone associated tumors. We present for the first time a therapeutic strategy targeting an epigenetic recognition protein of acetyl lysines in the bone associated tumor vicious cycle. Note: This abstract was not presented at the conference. Citation Format: Francois Lamoureux, Marc Baud'huin, Lidia Rodriguez, Camille Jacques, Francoise Redini, James E. Bradner, Dominique Heymann, Benjamin Ory. Selective inhibition of BET bromodomains epigenetic signaling interferes with the bone-associated tumor vicious cycle. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A50.