Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer.
Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer.
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DOI：
10.1158/0008-5472.can-10-2442
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Schrump DS
中科院分区：
文献类型：
--
作者：
Rao M;Chinnasamy N;Hong JA;Zhang Y;Zhang M;Xi S;Liu F;Marquez VE;Morgan RA;Schrump DS
癌症-睾丸抗原如NY-ESO-1、MAGE-A1和MAGE-A3是由基因编码的免疫原性蛋白，其通常仅在雄性生殖细胞中表达，但在人类肿瘤（包括肺癌）中通过不明确的表观遗传机制激活。以前，我们报告了这些癌症睾丸抗原在癌细胞中的诱导，而不是正常细胞，DNA去甲基化剂和组蛋白去乙酰化酶抑制剂使用临床上可实现的曝光条件。在本研究中，我们评估了与肺癌细胞中癌症睾丸基因的抑制/激活相关的染色质改变，以进一步开发用于癌症免疫治疗的基因诱导方案。NY-ESO-1、MAGE-A1和MAGE-A3的抑制与DNA超甲基化、polycomb组蛋白的募集和结合以及这些基因启动子内的组蛋白异染色质修饰相一致。去阻遏与DNA去甲基化、polycomb蛋白的解离以及各自启动子内常染色质标记的存在相一致。ShRNA用于抑制介导组蛋白甲基化和抑制基因表达的几种组蛋白甲基转移酶（KMT）和组蛋白脱甲基酶（KDM）。敲低KMT 6、KDM 1或KDM 5 B显著增强脱氧氮胞苷（DAC）介导的肺癌细胞中这些癌-睾丸基因的激活。DZNep是一种KMT 6表达的药理学抑制剂，它重现了KMT 6敲低的作用。在DAC-DZNep暴露后，肺癌细胞被表达识别NY-ESO-1和MAGE-A3的重组T细胞受体的同种异体淋巴细胞特异性识别和裂解。将DNA去甲基化剂与调节组蛋白赖氨酸甲基化的化合物如DZNep组合可以提供一种新的表观遗传策略，以增加癌症-睾丸基因表达作为过继性癌症免疫治疗的辅助手段。
Cancer-testis antigens such as NY-ESO-1, MAGE-A1 and MAGE-A3 are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells, but activated by ill-defined epigenetic mechanisms in human tumors including lung cancers. Previously we reported induction of these cancer-testis antigens in cancer cells, but not normal cells, by DNA demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer-testis genes in lung cancer cells to further develop gene induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment and binding of polycomb group proteins, and histone heterochromatin modifications within the promoters of these genes. De-repression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. ShRNAs were used to inhibit several histone methyl transferases (KMTs) and histone demethylases (KDMs) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1 or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer-testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knock-down. Following DAC-DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T cell receptors recognizing NY-ESO-1 and MAGE-A3. Combining DNA demethylating agents with compounds such as DZNep that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer-testis gene expression as an adjunct to adoptive cancer immunotherapy.