Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition.
Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition.
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DOI：
10.1158/2159-8290.cd-18-0385
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发表时间：
2018-11
期刊：
影响因子：
28.2
通讯作者：
MacPherson D
中科院分区：
文献类型：
--
作者：
Jia D;Augert A;Kim DW;Eastwood E;Wu N;Ibrahim AH;Kim KB;Dunn CT;Pillai SPS;Gazdar AF;Bolouri H;Park KS;MacPherson D
CREBBP编码乙酰转移酶，是小细胞肺癌（SCLC）中最常见的突变基因之一，SCLC是一种致命的神经内分泌肿瘤类型。我们报告了在本地小鼠模型中Crebbp失活后SCLC的加速。将这些观察结果扩展到肺之外，在小鼠神经内分泌细胞中广泛的Crebbp缺失与Rb 1/Trp 53缺失合作促进神经内分泌甲状腺和垂体癌。基因表达分析表明，Crebbp损失的结果在减少表达的紧密连接和细胞粘附基因，包括Cdh 1，跨神经内分泌肿瘤类型，而Cdh 1的抑制促进转化小细胞肺癌。CDH 1和其他粘附基因表现出减少组蛋白乙酰化与Crebbp失活。用组蛋白去乙酰化酶抑制剂Pracinostat处理增加组蛋白乙酰化并恢复CDH 1表达。此外，Rb 1/Trp 53/Crebbp缺陷型SCLC的一个亚组在体内对Pracinostat表现出异常应答。因此，CREBBP在SCLC中充当有效的肿瘤抑制剂，并且CREBBP的失活增强了对靶向治疗的反应。
CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, while suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. Additionally, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo. Thus, CREBBP acts as a potent tumor suppressor in SCLC and inactivation of CREBBP enhances responses to a targeted therapy.