BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell
| Autor: | De-Ying Liao, Cun-Dong Liu, Ji-Ming Bao, Mingkun Chen, Kang-Yi Xue, Yunlin Ye, Wen-Bin Guo, Jun-Hao Zhou, Zhi-Jian Liang, Zike Qin, Hai-Feng Duan, Ming Xia, Zhi-Peng Huang, Zi-Jian Chen, Jian-Kun Yang, Xiao Xie, Peng Wang, Yang Liu, Jia-Wei Zhou, Hong-Yi Wang, Cheng Yang, Qi-Zhao Zhou |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Aging ATP Binding Cassette Transporter Subfamily B Cell Survival medicine.medical_treatment Antineoplastic Agents Apoptosis macromolecular substances P-glycoprotein Deoxycytidine Cystectomy Histones Cell Line Tumor medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 Derepression Cisplatin Polycomb Repressive Complex 1 Bladder cancer biology Chemistry chemoresistance Cell Biology miR-3682-3p medicine.disease BMI1 Gemcitabine Gene Expression Regulation Neoplastic MicroRNAs Urinary Bladder Neoplasms Drug Resistance Neoplasm biology.protein Cancer research bladder cancer Female medicine.drug Research Paper |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| Popis: | Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer. |
| Databáze: | OpenAIRE |
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