Dysregulation of the Repressive H3K27 Trimethylation Mark in Head and Neck Squamous Cell Carcinoma Contributes to Dysregulated Squamous Differentiation
Dysregulation of the Repressive H3K27 Trimethylation Mark in Head and Neck Squamous Cell Carcinoma Contributes to Dysregulated Squamous Differentiation
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DOI：
10.1158/1078-0432.ccr-12-2505
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发表时间：
2013-01-15
影响因子：
11.5
通讯作者：
Saunders, Nicholas A.
中科院分区：
文献类型：
--
作者：
Gannon, Orla M.;de Long, Lilia Merida;Saunders, Nicholas A.
用途：头颈部鳞状细胞癌（HNSCC）是世界范围内最常见的癌症之一，5年生存率为55%。EZH 2是polycomb阻遏物复合物2的一种组分，使H3 K27（H3 K27 me 3）三甲基化，其已显示驱动正常角质形成细胞中的鳞状分化。本研究确定是否抑制EZH 2介导的表观遗传沉默可以诱导分化或提供治疗的好处，在HNSCC.Experimental Design：我们确定了抑制EZH 2的影响，无论是RNA干扰或RNAi，对HNSCC的生长，活力和分化在体外。结果：EZH 2在体外培养的HNSCC细胞系中高表达，组织芯片分析显示EZH 2在HNSCC细胞系（n = 59）中的原位表达高于正常口腔上皮（n = 12）。用siRNA抑制EZH 2可诱导分化难治性鳞状细胞癌细胞系中分化基因的表达。分化难治性HNSCC细胞系在分化基因的启动子上显示持续的H3 K27 me 3。DZNep除了显著降低集落形成效率和诱导一些鳞状分化基因外，还引起癌细胞特异性凋亡。此外，在体内，DZNep衰减在两个不同的异种移植模型中的肿瘤生长，引起肿瘤内抑制EZH 2，并诱导分化genes in situation.Conclusions：总的来说，这些数据表明，异常分化HNSCC可能是由于表观遗传失调，并表明PRC 2介导的基因抑制的抑制可能代表一个潜在的治疗靶点。Clin Cancer Res; 19（2）; 428-41. (C)2012年AACR。
Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers diagnosed worldwide and is associated with a 5-year survival rate of 55%. EZH2, a component of the polycomb repressor complex 2, trimethylates H3K27 (H3K27me3), which has been shown to drive squamous differentiation in normal keratinocytes. This study determined whether inhibition of EZH2-mediated epigenetic silencing could induce differentiation or provide therapeutic benefit in HNSCC.Experimental Design: We determined the effects of inhibiting EZH2, by either RNA interference or pharmacologically, on HNSCC growth, viability, and differentiation in vitro. Xenografts of HNSCC cell lines were used to assess efficacy of 3-deazaneplanocin A (DZNep), an inhibitor of H3K27 trimethylation, in vivo.Results: EZH2 was highly expressed in HNSCC cell lines in vitro and tissue microarray analysis revealed high expression in (n = 59) in situ relative to normal oral epithelium (n = 12). Inhibition of EZH2 with siRNA could induce expression of differentiation genes in differentiation-refractory squamous cell carcinoma cell lines. Differentiation-refractory HNSCC cell lines displayed persistent H3K27me3 on the promoters of differentiation genes. DZNep caused cancer-cell-specific apoptosis in addition to a profound reduction in colony-forming efficiency and induction of some squamous differentiation genes. Furthermore, in vivo, DZNep attenuated tumor growth in two different xenograft models, caused intratumor inhibition of EZH2, and induction of differentiation genes in situ.Conclusions: Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggest that inhibition of PRC2-mediated gene repression may represent a potential therapeutic target. Clin Cancer Res; 19(2); 428-41. (C) 2012 AACR.