CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy.
CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy.
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DOI：
10.1158/0008-5472.can-13-1659
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发表时间：
2014-04-01
期刊：
影响因子：
11.2
通讯作者：
Huang H
中科院分区：
文献类型：
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作者：
Ding L;Chen S;Liu P;Pan Y;Zhong J;Regan KM;Wang L;Yu C;Rizzardi A;Cheng L;Zhang J;Schmechel SC;Cheville JC;Van Deursen J;Tindall DJ;Huang H
尽管前列腺癌的发病率和死亡率很高，但这种疾病的病因尚未完全了解。在这项研究中，我们开发CBP和PTEN在前列腺癌中相互作用的功能证据，基于它们在人类疾病中的相关表达的发现。Cbppc−/−;Ptenpc+/−小鼠在前列腺中表现出更高的细胞增殖和早期发生的高级别前列腺上皮内瘤变。在小鼠Cbp−/−、Pten+/−和人前列腺癌细胞中，EZH 2甲基转移酶的水平沿着其Thr 350磷酸化水平增加。CBP缺失和PTEN缺陷协同触发从K27-乙酰化组蛋白H3到K27-三甲基化本体组蛋白的转换，其方式与生长抑制EZH 2靶基因DAB 2 IP、p27 KIP 1和p21 CIP 1的表达降低相关。相反，用组蛋白去乙酰化酶抑制剂帕比司他治疗逆转了这种转换，其方式与Cbppc−/−;Ptenpc+/−小鼠的肿瘤抑制有关。我们的研究结果显示CBP和PTEN如何相互作用以介导前列腺中的肿瘤抑制，建立组蛋白修饰在前列腺癌病因学中的核心作用，并为前列腺癌患者的表观遗传靶向治疗的临床评价提供了理论基础。
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients.