Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Neoplasia. 2011 Apr;13(4):374-85. doi: 10.1593/neo.101630.
Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh) signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor REN(KCTD11) acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two REN(KCTD11) homologues, defining a new family of proteins named KCASH, as "KCTD containing, Cullin3 adaptor, suppressor of Hedgehog." Indeed, the novel genes (KCASH2(KCTD21) and KCASH3(KCTD6)) share with REN(KCTD11) a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous "agents" through which this pathway may be targeted.
髓母细胞瘤是最常见的小儿脑恶性肿瘤，起源于小脑前体细胞发育异常，这一过程主要受 Hedgehog（Hh）信号通路的控制。组蛋白去乙酰化酶 HDAC1 最近被证明可以调节 Hh 信号，使Gli1/2 的效应物去乙酰化，并增强其转录活性。因此，HDAC 可能是 Hh 依赖性肿瘤的潜在治疗靶点，但关于 HDAC 调节的生理机制仍然知之甚少。假定的肿瘤抑制因子 REN（KCTD11）通过 HDAC1 的泛素化依赖性降解起作用，从而影响 Hh 活性和髓母细胞瘤的生长。我们在此鉴定并表征了两种 REN（KCTD11）同源物，定义了一个新的蛋白质家族，称为 KCASH，即“含 KCTD 的、Cullin3 接头、抑制 Hedgehog”。事实上，新基因（KCASH2（KCTD21）和 KCASH3（KCTD6））与 REN（KCTD11）共享多个特征，例如形成 Cullin3 泛素连接酶复合物所必需的 BTB 结构域，以及 HDAC1 的泛素化和降解能力，从而抑制了依赖乙酰化的 Hh/Gli 信号。KCASH2 和 -3 在小脑中有表达，而在人类髓母细胞瘤中观察到表观遗传沉默和等位基因缺失。恢复 KCASHs 的表达可减少 Hedgehog 依赖性髓母细胞瘤的生长，表明该家族新成员的缺失对于维持 Hh 通路介导的肿瘤发生至关重要。因此，它们可能代表了一类有前途的内源性“药物”，可以通过它们靶向该途径。
