PRIMA-1, a Mutant p53 Reactivator, Restores the Sensitivity of TP53 Mutant-Type Thyroid Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A
PRIMA-1, a Mutant p53 Reactivator, Restores the Sensitivity of TP53 Mutant-Type Thyroid Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A
复制标题
PRIMA-1 是一种突变型 p53 重激活剂，可恢复 TP53 突变型甲状腺癌细胞对组蛋白甲基化抑制剂 3-Deazaneplanocin A 的敏感性
DOI：
10.1210/jc.2013-3147
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发表时间：
2014-06-01
影响因子：
5.8
通讯作者：
Ji, Meiju
中科院分区：
文献类型：
--
作者：
Cui, Bo;Yang, Qi;Ji, Meiju
内容：3-去氮普兰诺星A（DZNep）耗尽zeste同源物2（EZH 2）的增强子，EZH 2是多梳抑制复合物2（PRC 2）的核心组分，其经常在人类癌症中过表达。DZNep具有良好的抗肿瘤活性，其在癌细胞中的反应性由某些遗传因素决定。目的：我们的目的是（1）测试DZNep的治疗潜力，并探索影响DZNep在甲状腺癌细胞中反应的遗传决定因素;（2）测试DZNep和PRIMA-1（突变型p53再激活剂）在甲状腺癌中的联合治疗效果。我们评估了DZNep在甲状腺癌细胞中的表型效应，并检测了DZNep单独或与PRIMA-1组合对细胞增殖、细胞周期、凋亡和异种移植瘤生长的影响。在所有甲状腺癌细胞中，TP 53（H3 K27 me 3）标记减少;然而，只有TP 53野生型细胞在DZNep处理下表现出生长抑制。在这些细胞中，DZNep通过上调USP 10表达引起p53蛋白积累，导致p53途径激活，有助于抑制细胞生长。相反，TP 53突变型细胞对DZNep具有抗性。令人惊讶的是，DZNep与PRIMA-1的组合恢复了TP 53突变型细胞对DZNep的敏感性。DZNep和PRIMA-1单独或联合应用的抗肿瘤作用在异种移植瘤模型中也观察到。结论：我们的数据表明，DZNep反应性与甲状腺癌细胞中TP 53基因组状态密切相关。p53的再活化恢复了TP 53突变型细胞对DZNep的敏感性。因此，联合治疗策略可以有效治疗携带突变型p53的甲状腺癌细胞（或患者）。
Context: 3-Deazaneplanocin A (DZNep) depletes enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2 (PRC2), which is frequently overexpressed in human cancers. DZNep exhibits promising antitumor activity, and its responsiveness in cancer cells is determined by certain genetic factors.Objectives: Our aims were (1) to test the therapeutic potential of DZNep and explore the genetic determinants affecting the DZNep response in thyroid cancer cells and (2) to test the combined therapeutic effect of DZNep and PRIMA-1, a mutant p53 reactivator, in thyroid cancer.Experimental Design: We evaluated the phenotypic effects of DZNep in thyroid cancer cells and examined the effects of DZNep alone or in combination with PRIMA-1 on cell proliferation, the cell cycle, apoptosis, and xenograft tumor growth.Results: DZNep induced enhancer of zeste homolog 2 depletion and trimethylated lysine 27 in H3 histone (H3K27me3) mark reduction in all thyroid cancer cells; however, only TP53 wild-type cells exhibited growth inhibition with DZNep treatment. In these cells, DZNep caused p53 protein accumulation through up-regulation of USP10 expression, resulting in activation of the p53 pathway, contributing to inhibition of cell growth. Conversely, TP53 mutant-type cells were resistant to DZNep. Strikingly, the combination of DZNep with PRIMA-1 restored the sensitivity of TP53 mutant-type cells to DZNep. A similar antitumor effect of DZNep and PRIMA-1 alone or in combination was also seen in xenograft tumor models.Conclusion: Our data demonstrated that DZNep responsiveness was strongly associated with TP53 genomic status in thyroid cancer cells. Reactivation of p53 restored the sensitivity of TP53 mutant-type cells to DZNep. Thus, a combined therapeutic strategy may be effective in treating thyroid cancer cells (or patients) harboring mutant p53.