Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children, consisting of four major subgroups (WNT, SHH, Group 3, and Group 4) that differ in genetic/epigenetic profiles and prognoses. Despite current therapy, a significant proportion of patients still succumb to MB. Moreover, survivors often suffer severe side effects from aggressive treatments. Therefore, improved strategies to treat MB are urgently needed. MB tumor cells retain the capacity for differentiation and can undergo terminal differentiation, after which they lose their proliferative and tumorigenic capacity. This suggests that MB can potentially be treated by inducing tumor cell differentiation. However, the mechanisms underlying MB tumor cell differentiation remain unclear. Our recent studies reveal that thyroid hormone (TH) plays a critical role in promoting tumor cell differentiation in MB. Reduced TH levels free the TH receptor, TRα1, to bind to EZH2 and repress the expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH levels reverse the EZH2-mediated repression of NeuroD1 by disrupting the binding between EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, triiodothyronine (T3, active form of TH) inhibits the growth of both SHH- and Group 3 tumors, suggesting that the tumor-inhibitory effect of T3 is not restricted by MB subgroups. Additionally, this effect is significantly enhanced by concurrent chemotherapy. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising therapeutic modality for MB treatment.