Department of Experimental Medicine, Sapienza University, 324 viale Regina Elena, 00161 Rome, Italy.
Nat Cell Biol. 2010 Feb;12(2):132-42. doi: 10.1038/ncb2013. Epub 2010 Jan 17.
Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.
Hedgehog 信号通路对发育至关重要，在包括髓母细胞瘤在内的几种肿瘤中失调。Gli（神经胶质瘤相关癌基因）蛋白转录活性的调节知之甚少，Gli 蛋白是 Hedgehog 通路的效应物。我们在这里表明，Gli1 和 Gli2 是乙酰化蛋白，它们的 HDAC 介导的去乙酰化作用通过 Hedgehog 诱导的 HDAC1 上调促进转录激活，并通过 Hedgehog 诱导的 HDAC1 上调维持正反馈回路。通过 Cullin3 和 REN 形成的 E3 泛素连接酶复合物，这种机制通过 HDAC1 降解而关闭，REN 是人类髓母细胞瘤中丢失的一种 Gli 拮抗剂。神经祖细胞和髓母细胞瘤中高 HDAC1 和低 REN 表达与活跃的 Hedgehog 信号相关，而 HDAC 活性丧失抑制 Hedgehog 依赖性神经祖细胞和肿瘤细胞的生长。与此一致的是，破坏 Gli1 乙酰化可增强细胞增殖和转化。这些数据确定了一个整合的 HDAC 和泛素介导的电路，其中 Gli 蛋白的乙酰化作为 Hedgehog 信号的一个意外关键转录检查点。
