Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway.
Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway.
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Hedgehog（Hh）通路的异常激活可驱动肿瘤发生。为了研究神经胶质瘤相关癌基因家族锌指-1（GLI 1）（Hh信号的关键效应子）调节Hh通路激活的机制，我们寻找GLI 1相互作用蛋白。我们报道了在人类恶性横纹肌样瘤（MRT）中失活的染色质重塑蛋白SNF 5（由SMARCB 1编码，以下称为SNF 5）与GLI 1相互作用。我们发现，Snf 5定位于Gli 1调节的启动子，并且Snf 5的丢失导致Hh-Gli通路的激活。相反，SNF 5在MRT细胞中的再表达抑制GLI 1。与此相一致，我们显示了在原代MRT中存在Hh-Gli激活的基因表达谱，并显示GLI 1在体外和体内驱动SNF 5缺陷MRT细胞的生长。因此，我们的研究揭示SNF 5是Hh信号传导的关键介质，并且GLI 1的异常激活是以前未描述的有助于MRT细胞生长的靶向机制。
Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling, regulates Hh pathway activation, we searched for GLI1-interacting proteins. We report that the chromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in human malignant rhabdoid tumors (MRTs), interacts with GLI1. We show that Snf5 localizes to Gli1-regulated promoters and that loss of Snf5 leads to activation of the Hh-Gli pathway. Conversely, re-expression of SNF5 in MRT cells represses GLI1. Consistent with this, we show the presence of a Hh-Gli–activated gene expression profile in primary MRTs and show that GLI1 drives the growth of SNF5-deficient MRT cells in vitro and in vivo. Therefore, our studies reveal that SNF5 is a key mediator of Hh signaling and that aberrant activation of GLI1 is a previously undescribed targetable mechanism contributing to the growth of MRT cells.
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