Targeting histone demethylase KDM6B for treatment of neuroblastoma

Abstract

Neuroblastoma is a cancer of the sympathetic neuron system that accounts for 15% of all childhood cancer-related deaths, an unusually high proportion based on the fact that it accounts for 7% of childhood malignancies. The survival rate for high-risk neuroblastoma is only 40% with current treatments including chemotherapy and radiation which cause unwanted side effects. There is growing interest to develop novel therapies by targeting epigenetic factors. KDM6B, a histone demethylase also known as JMJD3, is known to play a role in various types of cancer such as NOTCH1-mediated T-cell acute lymphoblastic leukemia. However, the role of KDM6B in neuroblastoma is largely unknown. Our previous studies indicate that KDM6B may serve as a new therapeutic target in neuroblastoma. We therefore hypothesize that pharmacologically targeting KDM6B could prove to be therapeutic in the treatment of neuroblastoma. To better understand the role of KDM6B, we utilized siRNA transfection and shRNA to inhibit KDM6B expression. We further tested a drug called GSK-J4 which targets the KDM6B protein. These studies have shown that genetic or pharmacologic inhibition of KDM6B could be a promising treatment for neuroblastoma, but more research is needed to understand the pathways involved.