The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.
The histone methyltransferase EZH2 is a therapeutic target in small cell carcinoma of the ovary, hypercalcaemic type.
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DOI：
10.1002/path.4912
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Huntsman DG
中科院分区：
文献类型：
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作者：
Wang Y;Chen SY;Karnezis AN;Colborne S;Santos ND;Lang JD;Hendricks WP;Orlando KA;Yap D;Kommoss F;Bally MB;Morin GB;Trent JM;Weissman BE;Huntsman DG
卵巢小细胞癌，高钙血症型，是一种罕见但侵袭性强且无法治疗的年轻女性恶性肿瘤。我们和其他人最近发现，SMARCA4是一个编码SWI/SNF染色质重塑复合体ATPase的基因，是大多数SCCOHT中唯一反复突变的基因。SCCOHT基因组的低体细胞复杂性和SWI/SNF染色质重塑复合体在基因转录调控中的重要作用表明，SCCOHT细胞可能依赖表观遗传重连进行致癌转化。在此，我们报告了大约80%(19/24)的SCCOHT肿瘤标本通过免疫组织化学方法强表达组蛋白甲基转移酶EZH2，其余的表达不同量的EZH2。SMARCA4的重新表达抑制了EZH2在SCCOHT细胞中的表达。与其他卵巢细胞株相比，SCCOHT细胞对EZH2 shRNAs和两种选择性EZH2抑制剂GSK126和EPZ-6438表现出超敏反应。EZH2抑制剂诱导SCCOHT细胞周期停滞、细胞凋亡和细胞分化，同时诱导参与细胞周期调控、细胞凋亡和神经元样分化的基因表达。EZH2抑制剂可抑制肿瘤生长并提高SCCOHT异种移植小鼠的存活率。因此，我们的数据表明，SMARCA4的缺失对EZH2在SCCOHT细胞中的催化活性具有依赖性，药物抑制EZH2是治疗这种疾病的一种有前途的治疗策略。
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodeling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodeling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation. Herein, we report that approximately 80% (19/24) of SCCOHT tumor samples have strong expression of the histone methyltransferase EZH2 by immunohistochemistry with the rest expressing variable amounts of EZH2. Re-expression of SMARCA4 suppressed the expression of EZH2 in SCCOHT cells. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to EZH2 shRNAs and two selective EZH2 inhibitors, GSK126 and EPZ-6438. EZH2 inhibitors induced cell cycle arrest, apoptosis, and cell differentiation in SCCOHT cells, along with the induction of genes involved in cell cycle regulation, apoptosis and neuron-like differentiation. EZH2 inhibitors suppressed tumor growth and improved the survival of mice bearing SCCOHT xenografts. Therefore, our data suggest that loss of SMARCA4 creates a dependency on the catalytic activity of EZH2 in SCCOHT cells and that pharmacological inhibition of EZH2 is a promising therapeutic strategy for treating this disease.
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哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
5.7
作者：
Chan-Penebre, Elayne;Armstrong, Kelli;Ribich, Scott A.
通讯作者：
Ribich, Scott A.
影响因子：
2.6
作者：
Estel, Rebecca;Hackethal, Andreas;Muenstedt, Karsten
通讯作者：
Muenstedt, Karsten
DOI：
10.1097/jto.0b013e318298762f
发表时间：
2013-08
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Hubaux R;Thu KL;Coe BP;MacAulay C;Lam S;Lam WL
通讯作者：
Lam WL
影响因子：
82.9
作者：
通讯作者：
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