Axis 1 - BET proteins and Super-Enhancers implications in chromatin and transcriptional regulation

ChromatIn and transcriptionaL Deregulation in pediatric bone sarcoma

Team leaders : Benjamin Ory et François Lamoureux

The aim of our research is now to understand the epigenetic mechanisms behind tumor resistance to treatment and metastatic process. This will be done by analyzing chromatin remodeling, gene activation and mapping of super-enhancer (SE) sites.

Histone modifications play a crucial role in controlling gene expression in both normal and cancer cells. The bromodomain and extra-terminal (BET) protein family is a significant group of "epigenetic reader" proteins that recognize H3K27ac. Our team showed that BET bromodomain signaling plays a role in osteosarcoma (OS) and that inhibition of this epigenetic recognition suppresses tumor growth both in vitro and in vivo (Nature Comm 2014, Oncotarget 2016). Importantly, our work provides a strong clinical rationale for the use of BET bromodomain inhibitors. We also demonstrated the implication of the BET in physiologic and pathologic (osteoporosis) bone development (Bone 2017, Epigenomics 2020).

An unequal distribution of BET and H3K27ac is detected in enhancer regions called super-enhancers (SEs). These SEs are linked to key genes that have a significant impact on normal cell biology and regulate the expression of transcription factors critical to tumor growth. Tumor cells may use SE-dependent chromatin structure and transcriptional regulation as an epigenetic mechanism to rapidly adapt and respond to treatment but also to spread to another site. This mechanism could make tumor cells more resistant to treatment and more metastatic capacities than the gradual evolution of random mutations, providing new targets for next-generation therapies.

We recently published a first paper demonstrating our ability to map the super-enhancers and to identify their transcriptional targets considering the chromatin structure. (in press, EHP 2023). Currently, we have identified in chemoresistant osteosarcoma cell lines two super-enhancers controlling gene transcription of two genes which are strongly involved in multi-drug resistance phenotype. We also mapped active SEs in osteosarcoma cell lines with different migratory capacities and detected three genes potentially strongly involved in pro-metastatic process. These results confirm that mapping of active SEs allows the identification of key genes that drive pro-tumor mechanisms. The efficacy of targeting these genes will be evaluated using preclinical models, including orthotopic and PDX models.