Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in neuroblastoma. Surgery 2015 Sep;158(3):819-26
Date
06/13/2015Pubmed ID
26067464Pubmed Central ID
PMC4536146DOI
10.1016/j.surg.2015.04.017Scopus ID
2-s2.0-84938961001 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
BACKGROUND: MYCN amplification is a key molecular hallmark of high-risk neuroblastoma. Previously considered an "undruggable" target, MYCN transcription can be disrupted by inhibiting the bromodomain and the extraterminal (BET) domain family of proteins that regulates MYCN transcription epigenetically. JQ1 is a potent, small-molecule BET inhibitor that induces cell-cycle arrest and initiates apoptosis in neuroblastoma. Here, we sought to validate the antitumorigenic effects of JQ1 in neuroblastoma and to evaluate whether blocking N-myc expression with JQ1 promotes neural differentiation.
METHODS: We determined the effects in vitro of JQ1 treatment on human neuroblastoma cell growth in both monolayer and sphere-forming conditions. Subcutaneous neuroblastoma xenografts were used for an in vivo study. Western blotting and immunohistochemistry were performed to evaluate the effects on neural differentiation and stem cell markers.
RESULTS: JQ1 treatment blocked neuroblastoma cell growth in both monolayer and sphere-forming conditions; JQ1 also attenuated the growth of neuroblastoma xenograft in athymic nude mice. Neurofilament expression was enhanced with JQ1 treatment, indicating that JQ1 induces neuronal differentiation. Sphere forming conditions resulted in increased expression of multiple stem cell markers; these effects were reversed with JQ1 treatment.
CONCLUSION: BET inhibition attenuates progression and promotes neural differentiation of neuroblastoma in vitro and in vivo in mice, providing insight into potential clinical applications of BET inhibitors in the treatment of patients with neuroblastoma.
Author List
Lee S, Rellinger EJ, Kim KW, Craig BT, Romain CV, Qiao J, Chung DHAuthor
Brian T. Craig MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Apoptosis
Azepines
Biomarkers, Tumor
Blotting, Western
Cell Line, Tumor
Cell Survival
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Male
Mice
Mice, Nude
N-Myc Proto-Oncogene Protein
Neuroblastoma
Neurogenesis
Nuclear Proteins
Oncogene Proteins
Random Allocation
Triazoles
Xenograft Model Antitumor Assays
