Regulation of OCT2 transcriptional repression by histone acetylation in renal cell carcinoma
Regulation of OCT2 transcriptional repression by histone acetylation in renal cell carcinoma
复制标题
肾细胞癌中组蛋白乙酰化对 OCT2 转录抑制的调节
DOI：
10.1080/15592294.2019.1615354
复制
发表时间：
2019-08-03
期刊：
影响因子：
3.7
通讯作者：
Zeng，Su
中科院分区：
文献类型：
--
作者：
Zhu，Qianying;Yu，Lushan;Zeng，Su
摘要肾细胞癌（RCC）是泌尿系统常见的恶性肿瘤，多药耐药是其化疗失败的主要原因之一。既往研究表明，人有机阳离子转运蛋白OCT2的缺失是导致肾细胞癌奥沙利铂耐药的主要因素，DNA甲基化和组蛋白甲基化在OCT2的转录抑制中起重要作用。在这项研究中，我们发现组蛋白乙酰化也调节肾癌中的OCT 2抑制，并阐明了潜在的机制。在正常肾细胞中，HDAC7在OCT 2启动子处与MYC结合，导致游离HDAC7减少，这反过来增加了OCT 2启动子处H3K18ac和H3K27ac的水平并激活OCT 2表达。然而，在RCC细胞中，HDAC7和MYC之间的相互作用不发生，这导致在OCT 2启动子处的HDAC7的高丰度和H3K18ac和H3K27ac的低水平，从而导致OCT 2转录的抑制。我们发现，使用DNA甲基化抑制剂地西他滨和组蛋白去乙酰化酶抑制剂伏立诺他的联合治疗显著增加了RCC细胞系中OCT 2的表达，从而使这些细胞对奥沙利铂敏感。因此，我们建议抗癌药物和表观遗传药物的组合可以提供一种新的化疗方案。
ABSTRACT Renal cell carcinoma (RCC) is a common malignant tumour affecting the urinary system, and multidrug resistance is one of the major reasons why chemotherapy for this type of cancer often fails. Previous studies have shown that loss of the human organic cation transporter OCT2 is the main factor contributing to oxaliplatin resistance in RCC, and that DNA hypermethylation and histone methylation play important roles in the transcriptional repression of OCT2 in RCC. In this study, we found that histone acetylation also regulates OCT2 repression in RCC and elucidated the underlying mechanisms. In normal renal cells, HDAC7 combines with MYC at the OCT2 promoter, resulting in a decrease in free HDAC7, which in turn increases the levels of H3K18ac and H3K27ac at the OCT2 promotor and activates OCT2 expression. In RCC cells, however, the interaction between HDAC7 and MYC does not occur, which leads a high abundance of HDAC7 and low levels of H3K18ac and H3K27ac at the OCT2 promoter, thereby resulting in the inhibition of OCT2 transcription. We found that combined treatment using the DNA methylation inhibitor decitabine and the histone deacetylase inhibitor vorinostat significantly increased the expression of OCT2 in RCC cell lines, which sensitized these cells to oxaliplatin. We accordingly propose that the combination of anticancer agents and epigenetic drugs can provide a novel chemotherapeutic regimen.