Neuroblastoma is the most common malignancy in infancy and the most common extracranial solid tumor in children. Approximately 50% of human malignancies are characterized by over-expression of oncogenic Myc oncoproteins including N-Myc and c-Myc. Myc oncoproteins induce the initiation and promote the progression of malignancies by modulating gene transcription, leading to cell proliferation.
The bromodomain and extra terminal (BET) family of proteins BRD3 and BRD4 have recently been shown to play critical roles in c-Myc gene transcription, and the BRD3/BRD4 inhibitors JQ1 and I-BET151 considerably reduce c-Myc gene transcription. Importantly, JQ1 and I-BET151 exert significant anticancer effects in mice xenografted with leukaemia, Burkitt's lymphoma and multiple myeloma, characterized by pathologic activation of c-Myc. Consequently, pharmaceutical companies are racing to test JQ1 in clinical trials.
Two neuroblastoma cell lines were treated with two bromodomain inhibitors, IBET151 and JQ1, and cellular viability and N-Myc gene expression were investigated. JQ1 and I-BET151 reduced cell viability as well as N-Myc mRNA and protein expression. The two bromodomain inhibitors also reactivated tumor suppressing genes including TP53INP1 gene and protein expression which is suppressed by N-Myc in N-Myc amplified nerublastoma cell lines.
Differential gene expression studies were performed with Affymetrix gene array in neuroblastoma cells 6 hours after treatment with vehicle control or JQ1. Analysis of the microarray data showed that two key oncogenic genes, BCL2 and MYB, were significantly repressed by JQ1. Further RT-PCR experiments also revealed that MYB and BCL2 mRNA expression was reduced over 24 hour treatment with JQ1.
In conclusion, Bromodomain inhibitors can be used as a therapeutic approach to target oncogenes including N-Myc, Bcl2 and Myb, and to reactivate the expression of tumour suppressor genes including TP53INP1.