Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines
Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines
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DOI：
10.1124/jpet.105.083956
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Chan, KK
中科院分区：
文献类型：
--
作者：
Xiao, JJ;Huang, Y;Chan, KK
组蛋白乙酰化状态是基因转录的表观遗传决定因素，由组蛋白乙酰转移酶（HAT）和组蛋白去乙酰化酶（HDAC）控制。有效的HDAC抑制剂FK 228 [（E）-（1 S，4S，10 S，21 R）-7-[（Z）-亚乙基]-4，21-二异丙基2-氧杂-12，13-二硫杂-5，8，20，23-四氮杂双环[8，7，6]-二十三-16-烯-3，6，9，22-戊酮]是多药耐药蛋白（MDR 1）和多药耐药相关蛋白1（MRP 1）的底物，两者都介导FK 228抗性。为了确定获得性FK 228耐药的机制，我们通过逐步增加FK 228暴露量，从HCT-15、IGROV 1、MCF 7和K562细胞中开发了4种FK 228耐药细胞系。使用70-寡聚体cDNA微阵列、实时逆转录-聚合酶链反应（RT-PCR）、Western印迹和细胞毒性测定来表征亲本和抗性细胞。在mRNA和蛋白质水平，MDR 1，而不是MRP 1或其他潜在的耐药基因，强烈上调，在所有耐药细胞系。HAT或HDAC活性在耐药细胞中不受影响，这与对不是MDR 1底物的HDAC抑制剂缺乏交叉耐药性一致。如实时RTPCR、Western印迹和染色质免疫沉淀所示，发现FK 228通过HDAC抑制和随后的MDR 1启动子组蛋白超乙酰化可逆诱导MDR 1表达。这项研究揭示了组蛋白乙酰化在MDR 1转录中的重要作用，这似乎介导了FK 228耐药。
Histone acetylation status, an epigenetic determinant of gene transcription, is controlled by histone acetyltransferases ( HATs) and histone deacetylases ( HDACs). The potent HDAC inhibitor FK228 [(E)-(1S, 4S, 10S, 21R)-7-[(Z)-ethylidene]-4,21-diisopropyl2- oxa-12,13-dithia- 5,8,20,23- tetraazabicyclo[ 8,7,6]- tricos-16- ene-3,6,9,22-pentanone] is a substrate for multidrug resistance protein (MDR1) and multidrug resistance-associated protein 1 (MRP1), both of which mediate FK228 resistance. To determine the mechanisms underlying acquired FK228 resistance, we developed four FK228-resistant cell lines from HCT-15, IGROV1, MCF7, and K562 cells by stepwise increases in FK228 exposure. Parent and resistant cells were characterized using a 70-oligomer cDNA microarray, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and cytotoxicity assays. At both mRNA and protein levels, MDR1, but not MRP1 or other potential resistance genes, was strongly up-regulated in all resistant cell lines. HAT or HDAC activities were unaffected in resistant cells, consistent with a lack of cross-resistance to HDAC inhibitors that are not MDR1 substrates. FK228 was found to reversibly induce MDR1 expression by HDAC inhibition and subsequent histone hyperacetylation at the MDR1 promoter, as shown by real-time RTPCR, Western blot, and chromatin immunoprecipitation. This study reveals a significant role of histone acetylation in MDR1 transcription, which seems to mediate FK228 resistance.