Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway
Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway
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DOI：
10.1158/1535-7163.mct-14-0481
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发表时间：
2015-03-01
影响因子：
5.7
通讯作者：
Lauth, Matthias
中科院分区：
文献类型：
--
作者：
Dhanyamraju, Pavan Kumar;Holz, Philipp Simon;Lauth, Matthias
失控的Hedgehog(HH)信号是几种恶性肿瘤的原因，包括儿童癌症髓母细胞瘤，一种影响小脑的神经外胚层肿瘤。尽管已经开发出有效的HH途径拮抗剂，但髓母细胞瘤的耐药性仍然是一个悬而未决的问题，需要寻找新的药物靶点。随着我们观察到组蛋白脱乙酰酶6(HDAC6)在HH驱动的髓母细胞瘤中表达增加，我们发现该酶对于HH途径的充分激活是必不可少的。有趣的是，HDAC6的这些刺激作用部分整合在初级纤毛下游，初级纤毛是一种已知的HDAC6调节结构。此外，HDAC6也是完全抑制基础HH靶基因表达所必需的。这些差异是通过HDAC60‘S对Gli2mRNA和Gli3蛋白表达的影响而实现的。由于这种与HH信号的复杂相互作用，全球转录组分析表明，HDAC6只调控Smoothed和Gli驱动的基因的一部分，包括所有成熟的HH靶标，如ptch1或Gli1。重要的是，体外抑制HDAC6可严重影响髓母细胞瘤细胞的存活，而在体内同种异体移植模型中，药物阻断HDAC6可显著降低肿瘤生长。总之，我们的数据描述了HDAC6在调节哺乳动物HH途径中的重要作用，并鼓励进一步关注HDAC6作为治疗髓母细胞瘤的新药物靶点的研究。(C)2014年AACR。
Uncontrolled Hedgehog (Hh) signaling is the cause of several malignancies, including the pediatric cancer medulloblastoma, a neuroectodermal tumor affecting the cerebellum. Despite the development of potent Hh pathway antagonists, medulloblastoma drug resistance is still an unresolved issue that requires the identification of novel drug targets. Following up on our observation that histone deacetylase 6 (HDAC6) expression was increased in Hh-driven medulloblastoma, we found that this enzyme is essential for full Hh pathway activation. Intriguingly, these stimulatory effects of HDAC6 are partly integrated downstream of primary cilia, a known HDAC6-regulated structure. In addition, HDAC6 is also required for the complete repression of basal Hh target gene expression. These contrasting effects are mediated by HDAC60's impact on Gli2 mRNA and GLI3 protein expression. As a result of this complex interaction with Hh signaling, global transcriptome analysis revealed that HDAC6 regulates only a subset of Smoothened-and Gli-driven genes, including all well-established Hh targets such as Ptch1 or Gli1. Importantly, medulloblastoma cell survival was severely compromised by HDAC6 inhibition in vitro and pharmacologic HDAC6 blockade strongly reduced tumor growth in an in vivo allograft model. In summary, our data describe an important role for HDAC6 in regulating the mammalian Hh pathway and encourage further studies focusing on HDAC6 as a novel drug target in medulloblastoma. (C) 2014 AACR.