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组蛋白去乙酰化酶抑制剂通过转录激活和mRNA稳定作用调节结直肠癌中P-糖蛋白的表达。

Histone deacetylase inhibitors regulate P-gp expression in colorectal cancer via transcriptional activation and mRNA stabilization.

作者信息

Wang Hao, Huang Cheng, Zhao Liang, Zhang Huan, Yang Jing Mo, Luo Peng, Zhan Bing-Xiang, Pan Qing, Li Jun, Wang Bao-Long

机构信息

Department of Clinical Laboratory, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China.

School of Pharmacy, Anhui Medical University, Hefei, China.

出版信息

Oncotarget. 2016 Aug 2;7(31):49848-49858. doi: 10.18632/oncotarget.10488.

DOI:10.18632/oncotarget.10488
PMID:27409663
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5226552/
Abstract

Histone deacetylase inhibitors (HDACIs) are emerging as a novel class of anti-tumor drugs. But the effect of HDACIs in tumors treatment has been disappointing, which mainly due to the acquisition of resistance to HDACIs. However, the underlying mechanisms have not been clearly understood. In this study, it was found that HDACIs SAHA and TSA increased P-gp expression in CRC cells, which has been well known to contribute to drug resistant. The mechanisms underlying these effects were investigated. We showed that HDACIs enhanced transcriptional activity of P-gp protein encoding gene ABCB1. HDACIs treatment also increased the protein and mRNA expression of STAT3, but not PXR, CAR, Foxo3a or β-catenin, which are known to be involved in ABCB transcription regulation. Interestingly, knockdown of STAT3 significantly attenuated HDACIs-induced P-gp up-regulation in colorectal cancer cells, suggesting that STAT3 plays a crucial role in HDACIs-up-regulated P-gp. Furthermore, this study revealed for the first time that HDACIs enhanced the stability of ABCB1 at post-transcriptional level. Taken together, these results proved that HDACIs induced P-gp expression by two distinct ways, transcriptional activation and mRNA stabilization. Our results suggested that more attention should be paid to the cancer treatment using HDACIs since they will induce multidrug resistance in cancer cells.

摘要

组蛋白去乙酰化酶抑制剂(HDACIs)正成为一类新型抗肿瘤药物。但HDACIs在肿瘤治疗中的效果一直令人失望,这主要是由于对HDACIs产生了耐药性。然而,其潜在机制尚未完全清楚。在本研究中,发现HDACIs SAHA和TSA可增加结直肠癌细胞中P-糖蛋白的表达,而P-糖蛋白已知与耐药性有关。对这些作用的潜在机制进行了研究。我们发现HDACIs增强了P-糖蛋白编码基因ABCB1的转录活性。HDACIs处理还增加了STAT3的蛋白和mRNA表达,但未增加已知参与ABCB转录调控的PXR、CAR、Foxo3a或β-连环蛋白的表达。有趣的是,敲低STAT3可显著减弱HDACIs诱导的结直肠癌细胞中P-糖蛋白的上调,表明STAT3在HDACIs上调P-糖蛋白过程中起关键作用。此外,本研究首次揭示HDACIs在转录后水平增强了ABCB1的稳定性。综上所述,这些结果证明HDACIs通过转录激活和mRNA稳定两种不同方式诱导P-糖蛋白表达。我们的结果表明,在使用HDACIs进行癌症治疗时应更加关注,因为它们会诱导癌细胞产生多药耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/b00360b98d90/oncotarget-07-49848-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/0eb1656ab8f4/oncotarget-07-49848-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/08b01f364d6d/oncotarget-07-49848-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/2fe79663c6d9/oncotarget-07-49848-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/58315a018abe/oncotarget-07-49848-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/20170cb106fe/oncotarget-07-49848-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/b00360b98d90/oncotarget-07-49848-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/0eb1656ab8f4/oncotarget-07-49848-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/08b01f364d6d/oncotarget-07-49848-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/2fe79663c6d9/oncotarget-07-49848-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/58315a018abe/oncotarget-07-49848-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/20170cb106fe/oncotarget-07-49848-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d197/5226552/b00360b98d90/oncotarget-07-49848-g006.jpg

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