Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy
Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy
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沉默表观遗传沉默子 KDM4A 用于 TRAIL 和 DR5 同时诱导和抗肿瘤治疗
DOI：
10.1038/cdd.2016.92
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发表时间：
2016-11-01
影响因子：
12.4
通讯作者：
Chen, Hong-Wu
中科院分区：
文献类型：
--
作者：
Wang, Junjian;Wang, Haibin;Chen, Hong-Wu
重组TRAIL和针对死亡受体（DR）的激动性抗体已经在临床试验中，但显示出有限的抗癌功效。肿瘤中缺乏功能性DR表达是一个主要的限制因素。我们在这里报告，染色质调节KDM 4A/JMJD 2A，而不是KDM 4 B，在沉默肿瘤细胞表达TRAIL及其受体DR 5中具有关键作用。在肺癌、乳腺癌和前列腺癌的TRAIL敏感和耐药癌细胞中，KDM 4A小分子抑制剂化合物-4（C-4）或基因沉默强烈诱导TRAIL和DR 5表达，并导致TRAIL依赖性凋亡细胞死亡。KDM 4A抑制也强烈地使细胞对TRAIL敏感。单独的C-4有效地抑制肿瘤生长，在治疗的肿瘤中显著诱导TRAIL和DR 5表达，并有效地使它们对新开发的TRAIL诱导剂ONC 201敏感。从机制上讲，C-4似乎不通过Akt-ERK-FOXO 3a途径起作用。相反，它通过解离KDM 4A和核受体辅阻遏物（NCoR）-HDAC复合物并诱导组蛋白乙酰化酶CBP的募集来切换TRAIL和DR 5转录激活因子CHOP基因启动子处的组蛋白修饰酶复合物。因此，我们的研究结果揭示了KDM 4A是肿瘤中TRAIL和DR 5的关键表观遗传沉默物，并建立了KDM 4A抑制剂作为有效使肿瘤对基于TRAIL途径的治疗敏感的新策略。
Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and-resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics.