Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle

Abstract

The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development.

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

“…9 Thus, BRD4 is a key regulator of the proliferation/apoptosis balance 12,13 by modulating gene expression and plays a critical role in post-DNA damage events. 17 In cancer, BRD4 is a known trigger of the osteogenic factor Runt-related transcription factor 2 expression, 18,19 which was recently associated with PAH lung abnormalities (including proliferation and calcification), 20 and, interestingly, BRD4 inhibition by JQ1 suppressed vascular calcification/atherogenic processes in a hypercholesterolemic murine model. 15 Furthermore, in addition to promoting DNA damage, 17 atherogenic processes 15 and increased proliferation, 12,13 BRD4 is also associated with inflammation, diabetes mellitus, obesity, and metabolic abnormalities, 13 all playing a role in VRDs, and particularly in coronary artery disease (CAD).…”

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

“…Since osteoporosis is an age-related disease, it could be speculated that those age-related changes in epigenetic marks participate in the pathophysiology of the disease [15]. Recent studies demonstrated JQ1 (a bromodomain inhibitor developed by the Structural Genomic Consortium) to suppress inflammation by a reduction of the inflammatory cytokine release, bone destruction by the inhibition of osteoclast maturation and bone formation by the inhibition of osteoblast maturation [15,16]. The latter activity makes its use for the treatment of osteoporosis questionable.…”

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

“…Besides bone formation, bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption, whereas the growth of long bones is from endochondral ossification of chondrocytes derived from cartilage (15). Previous studies have shown that BET inhibitors may affect osteoclastogenesis (14) and the bone-associated tumor vicious cycle (13). In this study, we demonstrated BET inhibitors as repressors of chondrogenesis.…”

“…In addition to this, multiple other BET inhibitors have been well studied and have revealed great potential for clinical application. For instance, (ϩ)-JQ1 suppresses breast cancer cells (31), gastric cancer cells (32), acute myeloid leukemia cells (33), and osteosarcoma cells (13). Furthermore, I-BET151 has been shown to induce cell apoptosis in myeloma and leukemia (16,34).…”

“…Pharmacological inhibition of BET proteins lowers the expression of key transcription factors such as oncogene c-MYC (8), clamps the transductions of PI3K signaling (9), inhibits Gli1 transcription and Hedgehog pathway (10), blocks transcription in neurons (11), represses VEGF-induced angiogenesis and vascular permeability (12), reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation (13), and restrains osteoclastogenesis (14). Meanwhile, potent BET inhibitors have been identified as showing antitumor efficacy in a number of preclinical cancer models in recent years, including leukemia, multiple myeloma, lymphoma, melanoma, and gastric cancer (15,16).…”