13-Cis Retinoic Acid Induces Neuronal Differentiation in Daoy (Medulloblastoma) Cells Through Epigenetic Regulation of Topoisomerase IIβ

Medulloblastoma (MB) is a malignant tumor of the cerebellum that occurs in children and infants. Abnormal neuronal differentiation can lead to brain tumors, and topoisomerase IIβ (Top IIβ) plays an important role in neuronal differentiation. The aim of this study was to investigate the molecular mechanism of 13-cis retinoic acid (13-cis RA) promoting the expression of Top IIβ and inducing neuronal differentiation in human MB Daoy cells. The results showed that 13-cis RA inhibited the cell proliferation and induced cell cycle arrest in G0/G1 phase. The cells differentiated into a neuronal phenotype, with high expression of the neuronal marker microtubule-associated protein 2 (MAP2) and abundant Top IIβ, and obvious neurite growth. Chromatin immunoprecipitation (ChIP) assay showed that histone H3 lysine 27 tri-methylation (H3K27me3) modification in Top IIβ promoter decreased after 13-cis RA-induced cell differentiation, while jumonji domain-containing protein 3 (JMJD3) binding in Top IIβ promoter increased. These results suggest that H3K27me3 and JMJD3 can regulate the expression of Top IIβ gene, which is related to inducing neural differentiation. Our results provide new insights into understanding the regulatory mechanisms of Top IIβ during neuronal differentiation and imply the potential application of 13-cis RA in the clinical treatment of MB.