MDR1 mediated chemoresistance: BMI1 and TIP60 in action.
MDR1 mediated chemoresistance: BMI1 and TIP60 in action.
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DOI：
10.1016/j.bbagrm.2016.06.002
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Bhattacharya R
中科院分区：
文献类型：
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作者：
Banerjee Mustafi S;Chakraborty PK;Naz S;Dwivedi SK;Street M;Basak R;Yang D;Ding K;Mukherjee P;Bhattacharya R
化疗诱导的耐药细胞的出现经常被观察到，并且以包括多药耐药蛋白 1 (MDR1) 在内的耐药蛋白家族的表达为例。然而，化疗诱导 MDR1 表达的简明机制尚不清楚。从机制上讲，突变选择、表观遗传改变、Wnt 通路激活或 p53 功能受损都与此有关。本研究描述了顺铂耐药细胞的存活部分共同上调了 MDR1、BMI1 和 TIP60 的乙酰转移酶活性。使用互补的功能获得和丧失方法，我们证明 MDR1 的表达受到 BMI1 的正向调节，BMI1 是一种传统上称为转录抑制因子的干细胞因子。我们的研究建立了 TIP60 和 BMI-1 之间的功能相互作用，导致 MDR1 表达上调。染色质免疫沉淀 (ChIP) 测定进一步确定近端 MDR1 启动子以 BMI1 依赖性方式对顺铂做出反应。 BMI1 与 MDR1 启动子上的一组 E-box 元件相互作用，并招募 TIP60，导致组蛋白 H2A 和 H3 乙酰化。总的来说，我们的数据在 MDR1、BMI1 和 TIP60 之间建立了迄今为止未知的联系，并为顺铂诱导的 MDR1 表达提供了机制见解，导致对紫杉醇、阿霉素和可能的其他药物产生交叉耐药。总之，我们的结果主张利用抗 BMI1 策略来减轻对化疗的获得性耐药。
Chemotherapy-induced emergence of drug resistant cells is frequently observed and is exemplified by the expression of family of drug resistance proteins including, multidrug resistance protein 1 (MDR1). However, a concise mechanism for chemotherapy-induced MDR1 expression is unclear. Mechanistically, mutational selection, epigenetic alteration, activation of the Wnt pathway or impaired p53 function have been implicated. The present study describes that the surviving fraction of cisplatin resistant cells co-upregulate MDR1, BMI1 and acetyl transferase activity of TIP60. Using complementary gain and loss of function approaches, we demonstrate that the expression of MDR1 is positively regulated by BMI1, a stem-cell factor classically known as a transcriptional repressor. Our study establishes a functional interaction between TIP60 and BMI-1 resulting in upregulation of MDR1 expression. Chromatin immunoprecipitation (ChIP) assays further establish that the proximal MDR1 promoter responds to cisplatin in a BMI1 dependent manner. BMI1 interacts with a cluster of E-box elements on the MDR1 promoter and recruits TIP60 resulting in acetylation of histone H2A and H3. Collectively, our data establish a hitherto unknown liaison among MDR1, BMI1 and TIP60 and provide mechanistic insights into cisplatin-induced MDR1 expression resulting in acquired cross-resistance against paclitaxel, doxorubicin and likely other drugs. In conclusion, our results advocate utilizing anti-BMI1 strategies to alleviate acquired resistance to chemotherapy.