Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma.
Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma.
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DOI：
10.1158/0008-5472.can-11-0046
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发表时间：
2011-07-01
期刊：
影响因子：
11.2
通讯作者：
Ellisen LW
中科院分区：
文献类型：
--
作者：
Ramsey MR;He L;Forster N;Ory B;Ellisen LW
鳞状细胞癌（SCC）是人类癌症的一种难治性亚型，起源于皮肤、肺、食道、口咽和其他组织的复层上皮。 SCC 的一个共同特征是 80% 的病例中 p53 相关蛋白 p63 (TP63) 高水平表达。 SCC 中表达的 p63 的主要蛋白质亚型是 ΔNp63α，这是一种 N 末端截短的形式，其作为关键的 SCC 细胞生存因子的功能尚不清楚。在这项研究中，我们证明 ΔNp63α 与 HDAC1 和 HDAC2 结合形成活性转录抑制复合物，可以靶向治疗优势。 p63/HDAC 对促凋亡 Bcl-2 家族成员基因（包括 PUMA）的抑制是 SCC 细胞存活所必需的。顺铂化疗是 SCC 治疗的主要手段，可促进 p63 和 HDAC 从 PUMA 启动子解离，导致组蛋白乙酰化、PUMA 激活和细胞凋亡增加。使用体外和体内模型，用 I/II 类 HDAC 抑制剂选择性靶向 p63/HDAC 复合物，重现了这些效应。对 HDAC 抑制的敏感性与 p63 表达直接相关，并且在过度表达内源性 Bcl-2 的肿瘤细胞中被消除。总之，我们的结果阐明了 p63 介导的转录抑制机制，并将 ΔNp63α/HDAC 复合物确定为 SCC 中重要的肿瘤维持因子。此外，我们的研究结果为应用 HDAC 抑制剂治疗鳞状细胞癌提供了理论依据。
Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium of the skin, lung, esophagus, oropharynx and other tissues. A unifying feature of SCC is high-level expression of the p53-related protein p63 (TP63) in 80% of cases. The major protein isoform of p63 expressed in SCC is ΔNp63α, an N-terminally truncated form which functions as a key SCC cell survival factor by mechanisms that are unclear. In this study we demonstrate that ΔNp63α associates with HDAC1 and HDAC2 to form an active transcriptional repressor complex that can be targeted to therapeutic advantage. Repression of pro-apoptotic Bcl-2 family member genes including PUMA by p63/HDAC is required for survival of SCC cells. Cisplatin chemotherapy, a mainstay of SCC treatment, promotes dissociation of p63 and HDAC from the PUMA promoter, leading to increased histone acetylation, PUMA activation and apoptosis. These effects are recapitulated upon targeting the p63/HDAC complex selectively with class I/II HDAC inhibitors using both in vitro and in vivo models. Sensitivity to HDAC inhibition is directly correlated with p63 expression and is abrogated in tumor cells that overexpress endogenous Bcl-2. Together, our results elucidate a mechanism of p63-mediated transcriptional repression and they identify the ΔNp63α/HDAC complex as an essential tumor maintenance factor in SCC. Additionally, our findings offer a rationale to apply HDAC inhibitors for SCC treatment.