Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma [RNA-seq]

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that requires long-term intensive multimodal therapies. Less than 50% survival rate of high-risk patients has prompted active and extensive studies to seek more effective therapies against MNA neuroblastomas but with few successes. We show that MYCN transdifferentiates the neuroblastoma cells from mesenchymal state to adrenergic state accompanied with induction of histone lysine demethylase 4 family members (KDM4A-C), all of which act in concert to control the expression of MYCN and adrenergic core regulatory transcription factors (CRC TF). Pharmacologic inhibition of KDM4 blocks expression of MYCN and adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against MNA neuroblastomas by inducing differentiation, apoptosis and type I interferon response. KDM4 inhibition in combination with chemotherapy leads to complete tumor response of MNA xenografts, without overt toxicity in animals. Thus, KDM4 blockade may be a transformative strategy to target the dependency of adrenergic CRC TFs in MNA neuroblastomas. Overall design: In order to verify MYCN alters the mesenchymal state of neuroblastoma cells to a more adrenergic state, we generated MYCN inducible GIMEN cell line. Then, we performed gene profiling analysis with RNA-seq data. For exploring the KDM4 protein role in the neuroblastoma cells, we treated GIMEN, SH_SY5Y with QC6352, also generated QC6352-resistant BE2C cells. We investigated the tumor samples from TH-MYCN/ALKF1178L mouse model with and without QC6352 treatment. We compare gene profiles changes with or without QC6352 treatment or QC6352 resistant.