Circ_0004087 interaction with SND1 promotes docetaxel resistance in prostate cancer by boosting the mitosis error correction mechanism.
Circ_0004087 interaction with SND1 promotes docetaxel resistance in prostate cancer by boosting the mitosis error correction mechanism.
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DOI：
10.1186/s13046-022-02404-3
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发表时间：
2022-06-03
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对微管靶向药物多西他赛（DTX）的耐药性一直是转移性去势抵抗性前列腺癌（mCRPC）治疗的巨大障碍。最近，针对有丝分裂错误校正机制的策略，包括染色体乘客复合物（CPC）被报道可以逆转对微管靶向抗癌药物的耐药性。同时，越来越多的证据表明circRNA在前列腺癌（PCa）的DTX耐药中起重要作用。然而，circRNA是否可以通过影响有丝分裂错误校正机制来调节DTX化学敏感性仍不清楚。通过挖掘公共circRNA数据集并进行蛋白质印迹和qRT-PCR测定来确定circ_0004087和BUB 1的表达模式。进行琼脂糖凝胶电泳、桑格测序和RNase R处理以检查circ_0004087的环状特征。进行了CircRNA下拉、质谱分析、Co-IP和双荧光素酶报告基因测定，以揭示circ_0004087、SND 1和MYB之间的相互作用。通过流式细胞术和在异种移植肿瘤模型上的体内药物研究来探索circ_0004087和BUB 1对基于紫杉醇的化疗的影响。在本研究中，我们揭示了一种新的circRNA（circ_0004087）与有丝分裂错误纠正机制之间的深刻相互作用。从机制上讲，circ_0004087与转录共激活因子SND 1结合可以刺激MYB的反式激活，并增强下游靶点BUB 1的表达。反过来，BUB 1表达的升高进一步将CPC募集到着丝粒，并保证PCa细胞的无错误有丝分裂。在生物学上，circ_0004087的过表达赋予PCa细胞中的DTX抗性，而敲低削弱PCa细胞中的DTX抗性。我们的研究揭示了circ_0004087/SND 1/MYB/BUB 1轴在调节错误有丝分裂纠正机制和DTX化疗耐药性中的关键作用，表明circ_0004087可能作为有价值的预后生物标志物和潜在的治疗靶点在DTX耐药的PCa患者中。在线版本包含补充材料，可通过10.1186/s13046-022-02404-3获得。
Acquisition of the chemoresistance to docetaxel (DTX), a microtubule-targeting agent, has been a huge obstacle in treatment for metastatic castration-resistant prostate cancer (mCRPC). Recently, strategies targeting the mitosis error correction mechanism including chromosomal passenger complex (CPC) were reported to reverse the resistance to microtubule-targeting anticancer agents. Meanwhile, accumulating evidence indicated the important roles of circRNAs in DTX resistance of prostate cancer (PCa). However, whether circRNAs could regulate DTX chemosensitivity by affecting the mitosis error correction mechanism remains unclear. Expression patterns of circ_0004087 and BUB1 were determined through mining the public circRNA datasets and performing western blot and qRT-PCR assays. Agarose gel electrophoresis, Sanger sequencing, and RNase R treatment were conducted to examine the circular characteristics of circ_0004087. CircRNA pull-down, mass spectrometry analysis, Co-IP, and dual-luciferase reporter assays were performed to uncover the interaction among circ_0004087, SND1, and MYB. The effects of circ_0004087 and BUB1 on docetaxel-based chemotherapy were explored by flow cytometry and in vivo drug studies upon xenografted tumor model. In the present study, we revealed the profound interaction between a novel circRNA, circ_0004087, and the mitosis error correction mechanism. Mechanistically, circ_0004087 binding with transcriptional coactivator SND1 could stimulate the transactivation of MYB and enhance the expression of downstream target BUB1. In turn, elevated BUB1 expression further recruited CPC to centromeres and guaranteed the error-free mitosis of PCa cells. Biologically, the overexpression of circ_0004087 conferred while the knockdown impaired DTX resistance in PCa cells. Our study uncovered the crucial role of circ_0004087/SND1/MYB/BUB1 axis in modulating the error mitosis correction mechanism and DTX chemoresistance, suggesting that circ_0004087 may serve as a valuable prognostic biomarker and a potential therapeutic target in DTX-resistant PCa patients. The online version contains supplementary material available at 10.1186/s13046-022-02404-3.
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DOI：
10.3390/molecules26071981
发表时间：
2021-04-01
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Borah NA;Reddy MM
通讯作者：
Reddy MM
DOI：
10.1093/bioinformatics/btt495
发表时间：
2013-11-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Agostini F;Zanzoni A;Klus P;Marchese D;Cirillo D;Tartaglia GG
通讯作者：
Tartaglia GG
影响因子：
14.9
作者：
Li CL;Yang WZ;Chen YP;Yuan HS
通讯作者：
Yuan HS
影响因子：
23.4
作者：
Francini, Edoardo;Sweeney, Christopher J.
通讯作者：
Sweeney, Christopher J.
影响因子：
6.6
作者：
Cookson, Michael S.;Lowrance, William T.;Kibel, Adam S.
通讯作者：
Kibel, Adam S.