Different involvement of promoter methylation in the expression of organic cation/carnitine transporter 2 (OCTN2) in cancer cell lines.
Different involvement of promoter methylation in the expression of organic cation/carnitine transporter 2 (OCTN2) in cancer cell lines.
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启动子甲基化对癌细胞系中有机阳离子/肉碱转运蛋白 2 (OCTN2) 表达的不同参与
DOI：
10.1371/journal.pone.0076474
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhou HH
中科院分区：
文献类型：
--
作者：
Qu Q;Qu J;Zhan M;Wu LX;Zhang YW;Lou XY;Fu LJ;Zhou HH
有机阳离子/肉碱转运体2(OCTN2)负责细胞摄取抗肿瘤药物奥沙利铂。表观遗传修饰是肿瘤中药物转运体表达改变的可能机制，导致化疗药物疗效改变。然而，控制OCTN2调控的机制并不完全清楚。在本研究中，去甲基化试剂地西他滨(DCA)提高了HepG2和LS174T细胞低水平的OCTN_2水平。为了进一步揭示OCTN2下调的表观遗传学机制，我们在荧光素酶报告实验中发现OCTN2启动子内的区域1(跨越−354到+85)是OCTN2表达的决定因素。此外，甲基化特异性聚合酶链式反应(MSP)和亚硫酸氢盐基因组测序显示，该区域内单个CpG位点的甲基化程度与不同癌细胞中OCTN2的水平呈负相关。将DCA应用于HepG2和LS174T细胞，逆转了OCTN2启动子的高甲基化状态，增加了OCTN2的表达，提高了细胞对奥沙利铂的摄取。因此，我们确定启动子甲基化是导致在HepG2和LS174T细胞中OCTN2的表观遗传下调的原因。鉴于OCTN2在癌细胞摄取化疗药物和治疗效果方面的重要作用，用去甲基化试剂进行预处理是优化抗癌药物治疗的一种可能策略。
Organic cation/carnitine transporter 2 (OCTN2) is responsible for the cellular uptake of the antineoplastic agent, oxaliplatin. Epigenetic modification is a possible mechanism of altered drug-transporter expression in cancers, leading to altered efficacy of chemotherapeutic drugs. However, the mechanisms governing OCTN2 regulation are not completely understood. In this study, the low levels of OCTN2 in HepG2 and LS174T cells were elevated by the demethylating reagent, decitabine (DCA). To further reveal the epigenetic mechanism of down-regulation of OCTN2, we found that Region-1 within the OCTN2 promoter (spanning −354 to +85) was a determinant of OCTN2 expression in a luciferase reporter assay. Moreover, methylation-specific PCR (MSP) and bisulfite genomic sequencing showed that the degree of individual methylated CpG sites within this region was inversely correlated with the levels of OCTN2 in different cancer cells. Application of DCA to HepG2 and LS174T cells reversed the hypermethylation status of the OCTN2 promoter and increased OCTN2 expression, enhancing cellular uptake of oxaliplatin. Thus, we identified that promoter methylation is responsible for epigenetic down-regulation of OCTN2 in HepG2 and LS174T cells. Given the essential role of OCTN2 in cancer cell uptake of chemotherapeutics, and thus treatment efficacy, pretreatment with a demethylating reagent is a possible strategy for optimizing pharmacotherapies against cancers.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
DOI：
10.1006/bbrc.1998.8669
发表时间：
1998-05-29
影响因子：
3.1
作者：
Wu, X;Prasad, PD;Ganapathy, V
通讯作者：
Ganapathy, V
影响因子：
12.3
作者：
Schaeffeler E;Hellerbrand C;Nies AT;Winter S;Kruck S;Hofmann U;van der Kuip H;Zanger UM;Koepsell H;Schwab M
通讯作者：
Schwab M
影响因子：
3.9
作者：
Kano, Takashi;Kato, Yukio;Tsuji, Akira
通讯作者：
Tsuji, Akira
影响因子：
9.8
作者：
Shoji, Y;Koizumi, A;Takada, G
通讯作者：
Takada, G