Thyroid Hormones Promotes Terminal Differentiation of Medulloblastoma Tumor Cells
Hypothyroidism is commonly detected in patients with medulloblastoma (MB), a pediatric brain tumor, which is generally considered as a treatment-related complication. Although reduced levels of thyroid hormone (TH) significantly correlate with poor survival of patients with MB, the possible link between TH signaling and MB pathogenicity is unknown. Here, we found that TH regulating terminal differentiation of tumor cells. Reduction in the levels of TH frees the unliganded TH receptor, TRa, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives terminal differentiation of neuronal progenitors as well as MB cells. Moreover, TH promotes extensive differentiation and reduced proliferation of tumor cells from multiple molecular subtypes of MB including the hedgehog (HH) group as well as group 3 (G3) MB. Consequently, TH treatment significantly inhibits the in vivo growth of SHH- and G3-MB by promoting tumor cell differentiation, with no obvious increase in tumor cell death, indicating that TH signaling represents a novel therapeutic entry-point for broad treatment of MB. Overall design: We assess the genetic profiles of tumor cells. Tumor cells from mice with conditional deletion of Ptch1, an established model for SHH-MB, were treated with T3 or PBS, by RNA sequencing. KEGG pathway analyzy neuronal differentiation related pathways. The neuronal differentiation associated genes and SHH pathway target genes was analyzed as well. RNA sequencing on tumor cells from mice with conditional deletion of Ptch1, an established model for SHH-MB, as well as human PDOX Shh and Group3 subtypes were assessed for comparisons between T3 treatments and PBS controls.