Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2
| Autor: | Guozhong Yi, Lei Yu, Ziyang Chen, Jun Pan, Songtao Qi, Shengze Deng, Guang-long Huang, Yaomin Li, Wei Xiang, Yawei Liu, Zhiyong Li, Xi-an Zhang, Bingxi Lei, Manlan Guo, Hai Wang |
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| Rok vydání: | 2019 |
| Předmět: |
Cytoplasmic Dyneins
0301 basic medicine Methyltransferase DNA Repair DNA repair DNA damage XPC Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Temozolomide medicine acquired TMZ resistance Animals Humans Gene silencing Antineoplastic Agents Alkylating DNA Modification Methylases neoplasms Gene knockdown Brain Neoplasms Tumor Suppressor Proteins glioblastoma O-6-methylguanine-DNA methyltransferase Original Articles DHC2 digestive system diseases DNA Repair Enzymes 030104 developmental biology chemistry CBX5 Chromobox Protein Homolog 5 Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Heterografts Neurology (clinical) DNA medicine.drug |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awz202 |
| Popis: | The mechanisms by which MGMT-deficient glioblastomas acquire resistance to temozolomide are unclear. Yi et al. show that retrograde nuclear transportation of the DNA damage repair proteins XPC and CBX5 confers temozolomide resistance in MGMT-deficient glioblastoma cells. Development of DHC2 inhibitors could be a promising strategy for overcoming acquired temozolomide resistance. The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma. |
| Databáze: | OpenAIRE |
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