IBMS BoneKEy | BoneKEy Watch
Therapeutic inhibition of BET bromodomain signaling in osteosarcoma
DOI:10.1038/bonekey.2014.85
Investigating the molecular basis of the vicious cycle of bone destruction that is a prelude to osteosarcoma progression, Lamoureux et al. demonstrate the importance of signaling between proteins that belong to the bromodomain and extra-terminal domain (BET) family. This family includes BRD2, BRD3, BRD4 and BRDT.
The researchers first demonstrated a significant reduction in BET bromodomain signaling in vitro in osteosarcoma cells treated with the inhibitor JQ1. Use of the inhibitor in two in vivo models also showed a dramatic inhibition of osteosarcoma growth. JQ1 was shown to downregulate expression of MYC. Furthermore, inhibiting BET-bromodomain signaling led to removal of BRD4 from the RUNX2 promoter, a major transcription factor known to be important in osteosarcoma development.
Finally, in vivo studies in mice with experimentally induced primary bone tumours initiated by the implantation of POS-1 tumour cells confirmed that treatment with JQ1 dramatically reduced tumor progression and significantly prolonged survival. Micro CT scanning confirmed that the treated mice showed a reduced level of bone destruction associated with the tumour.
JQ1 inhibits osteoclast and osteoblast differentiation; its action on osteoclast progenitors seems to be mediated by RANKL-associated BRD4-dependent activation of NFATC1 transcription. NFATC1 is a major controller of osteoclast differentiation.
Editor’s comment: This study provides strong evidence that inhibition of BET bromodomain signalling in osteosarcoma simultaneously targets the tumor and the bone microenvironment that supports tumor growth. BET inhibitors appear to be promising therapeutic agents for malignant bone disease.
This work is licensed under a
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.