摘要
背景：DNA甲基化剂的表观遗传联合和组蛋白脱乙酰酶抑制剂（HDAC）在治疗非小细胞肺癌（NSCLC）时表现出了临床优势。然而，很少有研究揭示其联合治疗的分子机制。之前的研究表明，DNA的甲基化试剂氮胞苷（AZA）在配对盒基因5（PAX5）启动子区使CpG位点去甲基化，但不诱导PAX5的mRNA和蛋白的表达。 方法：本研究采用Aza和HDAC抑制剂的表观遗传联合Vorinostat (SAHA)来治疗非小细胞肺癌细胞并研究及其分子机制。我们用亚毒性浓度的Aza+SAHA联合剂处理PAX5抑制的非小细胞肺癌H460细胞并检测pax5 mNRA和蛋白质的重新表达。 结果：实验结果表明： Aza 治疗使CpG位点的启动子区域的PAX5位点去甲基化，SAHA使得蛋白质结合的DNA可及性增加。 Aza+SAHA的联合治疗显著增加PAX5基因启动子区p53蛋白与DNA的结合（P＜0.01）。转录因子p53与PAX5基因启动子区的有效的结合，可能是因为 SAHA增加了染色质构象性结合性和氮甲基化DNA的包容性，允许转录因子结合。 结论：我们的研究不仅解释了Aza+SAHA联合治疗通过p53诱导使得H460细胞中PAX5重新表达，也证明了去甲基化剂和HDAC抑制剂的结合可以重新激活肿瘤抑制基因（TSG），该基因与转录因子结合到TSG启动子区的增强有关 。
关键词: 表观遗传学，HDAC，甲基化，非小细胞肺癌， pax5抗体
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