Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA 19111, USA; Cancer Epigenetic Institute, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA 19111, USA.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cancer Cell. 2024 Aug 12;42(8):1434-1449.e5. doi: 10.1016/j.ccell.2024.07.008.
Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.
甲状腺功能减退症在髓母细胞瘤（MB）患者中很常见。然而，甲状腺激素（TH）是否有助于 MB 的发病机制仍未确定。在这里，我们发现 TH 在促进肿瘤细胞分化中起着关键作用。TH 水平的降低使 TH 受体 TRα1 能够与 EZH2 结合，并抑制转录因子 NeuroD1 的表达，NeuroD1 驱动肿瘤细胞分化。增加 TH 通过消除 EZH2 和 TRα1 的结合来逆转 EZH2 介导的 NeuroD1 抑制，从而刺激肿瘤细胞分化并减少 MB 的生长。重要的是，TH 诱导的肿瘤细胞分化不受 MB 分子亚群的限制，这表明 TH 可广泛用于治疗 MB 亚群。这些发现确立了 TH 信号与 MB 发病机制之间前所未有的关联，为 TH 作为 MB 治疗的一种有前途的方式提供了确凿的证据。
