组蛋白去乙酰化酶抑制剂对肺癌细胞株MDR1、MRP1表达的影响及其机制

Effects of histone deacetylase inhibitor on expression of MDR1 and MRP1 in lung cancer cells

目的观察组蛋白去乙酰化酶抑制剂对肺癌细胞中多药耐药基因1(MDR1)和多药耐药相关蛋白1(MRP1)表达的影响,并探讨其机制。方法采用组蛋白去乙酰化酶抑制剂伏瑞斯特(SAHA)、曲古抑菌素A(TSA)刺激肺癌细胞A549、SK-mes-1,实时定量PCR法检测MDR1和MRP1基因,Western blotting法检测MDR1、MRP1蛋白及组蛋白去乙酰化酶1、2、3、4(HDAC1、2、3、4)和组蛋白H3甲基化(2MeH3K9)。结果 SAHA和TSA可以提高SK-mes-1、A549细胞中MDR1基因和蛋白的表达,抑制MRP1基因和蛋白表达(P均<0. 05); SAHA和TSA抑制了HDAC3、HDAC4表达,提高了2MeH3K9表达(P均<0. 05)。结论 SAHA和TSA促进了肺癌细胞中MDR1表达并抑制了MRP1表达,其中涉及的机制可能是SAHA和TSA同时促进了组蛋白的乙酰化和甲基化,从而调控了MDR1和MRP1的不同表达。

Objective To investigate the effects and mechanism of histone deacetylase inhibitor on the expression of multidrug resistance gene-1(MDR1)and multidrug resistance-associated protein 1(MRP1)in the lung cancer cells.Methods The mRNA expression of MDR1 and MRP1 in A549 and SK-mes-1 cells treated by SAHA and TSA were detected by RT-PCR.The protein expression of MDR1 and MRP1 in the A549 and SK-mes-1 cells treated by SAHA and TSA,and the expression of HDAC1,-2,-3,-4,and 2MeH3K9 in the A549 cells treated by SAHA and TSA was detected by Western blotting.Results SAHA and TSA increased the mRNA and protein expression of MDR1 but decreased the mRNA and protein expression of MRP1 in the A549 and SK-mes-1 cells(both P<0.05).SAHA and TSA increased 2MeH3K9 expression and decreased HDAC3 and HDAC-4 expression in the A549 cells(both P<0.05).Conclusion SAHA and TSA promote the MDR1 expression and inhibits the MRP1 expression in the lung cancer cells by simultaneously promoting the acetylation and methylation of histones.