Abstract 4673: BET bromodomains epigenetic signaling in osteosarcoma: Localization of super-enhancers and identification of new therapeutic targets
Authors: Lavaud Melanie , Tesfaye Robel , Georges Steven , Baud'huin Marc , Lamoureux François ,   BENJAMIN ORY
Published: September 2020

Abstract
Bone pathologies exhibit diverse and often combined genetic, hormonal, inflammatory and environmental origins. These pathologies (osteopetrosis, osteolysis expensive, Paget ‘s disease, osteoporosis, rheumatoid arthritis, bone cancer…), affecting altogether millions peoples around the world, correspond to local or generalized imbalance of the differentiation/function of cells in charge of bone apposition (osteoblasts) and bone resorption (osteoclasts). Therefore, the identification of new mechanisms and new therapeutic targets constitute a major clinical challenge to improve patients' care and to ameliorate their clinical outcome. Osteosarcoma (OS) is the most frequent primary bone tumor in children and adolescents. Despite advances in treatment such as multi-agent chemotherapy, patients with metastases or those whose tumors are refractory to chemotherapy continue to have a poor prognosis. Except frequent mutations of the p53 and Rb genes, no oncogenic drivers have been identified for OS. Therefore, it becomes necessary to explore possible epigenetic origins of OS development and combinations of unknown oncogenes expression at the origin of OS development in order to develop innovative therapeutic approaches to improve the medical response of OS. Histone modifications are of critical importance for the maintenance of the transcription program of normal cells. The bromodomain and extra-terminal domain (BET) protein family is an important class of “epigenetic reader proteins”. Bromodomain-containing proteins act as a scaffold for molecular complexes at recognized histones sites in order to regulate chromatin accessibility to transcription factors and RNA polymerase. We recently showed that BET bromodomain signaling plays a role in bone and osteosarcoma and that inhibition of this epigenetic recognition pathway suppresses osteosarcoma tumor growth both in vitro and in vivo.Interestingly, recent studies have identified an asymmetric distribution of BRD4 (BET protein) at enhancer regions across the epigenome, the so-called super-enhancers. These super-enhancers are associated with key cell type specific genes known to play prominent roles in the biology of normal cells and with oncogenic drivers in tumor cells. Thus, JQ1 was shown to reduce the transcription of such genes, whose expression is more sensitive to the presence of BET bromodomains.Those super enhancers (highly enriched for BET proteins) are present differentially depending on the cell type in order to activate specific transcriptional program for each cell type and context.Our study has investigated the super-enhancer organization in bone cancer biology. We elucidate the potential roles and organization of the BET bromodomain protein (and localized super-enhancers) in normal and tumoral bone in order to identify new therapeutic targets.
Citation Format: Melanie Lavaud, Robel Tesfaye, Steven Georges, Marc Baud'huin, François Lamoureux, BENJAMIN ORY. BET bromodomains epigenetic signaling in osteosarcoma: Localization of super-enhancers and identification of new therapeutic targets [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4673.