The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma
The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma
复制标题
DOI：
10.1080/15384101.2015.1090063
复制
发表时间：
2015-11-02
期刊：
影响因子：
4.3
通讯作者：
Romani, Massimo
中科院分区：
文献类型：
--
作者：
Banelli, Barbara;Carra, Elisa;Romani, Massimo
尽管目前的多模式治疗，包括手术，放疗和化疗与替莫唑胺（TMZ），胶质母细胞瘤（GBM）患者的中位生存期约为14个月，由于细胞克隆耐药的快速出现。因此，了解化疗耐药性的潜在机制对于改善治疗结果至关重要。我们从GBM细胞系和从人GBM分离的富含癌症干细胞的培养物中产生TMZ抗性细胞（TMZ-R）。我们证明，TMZ耐药性部分逆转的药物洗脱表明，在耐药性的表观遗传机制的贡献，并支持TMZ再激发GBM患者在既往药物暴露后的可能性。与亲本细胞相比，TMZ-R细胞中组蛋白赖氨酸脱甲基酶基因（KDM）的表达增加，并且通过过表达或灭活KDM 5A来模拟TMZ抗性或恢复的敏感性。与亲代TMZ敏感细胞相比，TMZ-R细胞中O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的甲基化和表达以及药物外排机制未发生改变。TMZ-R细胞瞬时获得分化肿瘤细胞的形态和分子特征，这些特征在药物洗脱后丢失。总之，我们证明了治疗诱导的TMZ耐药GBM涉及表观遗传机制在一个子集的慢循环和短暂的部分分化的细胞逃避药物的细胞毒性，克服G2检查点和维持克隆生长。我们发现TMZ-R细胞对与TMZ协同作用的组蛋白去乙酰化酶抑制剂（HDACi）敏感。这种强大的协同作用可以用来开发新的联合辅助治疗这种快速进展和总是致命的癌症。
Notwithstanding current multimodal treatment, including surgery, radiotherapy and chemotherapy with temozolomide (TMZ), median survival of glioblastoma (GBM) patients is about 14months, due to the rapid emergence of cell clones resistant to treatment. Therefore, understanding the mechanisms underlying chemoresistance is mandatory to improve treatments' outcome. We generated TMZ resistant cells (TMZ-R) from a GBM cell line and from cancer stem cell-enriched cultures isolated from human GBMs. We demonstrated that TMZ resistance is partially reverted by drug wash-out suggesting the contribution of epigenetic mechanisms in drug resistance and supporting the possibility of TMZ rechallenge in GBM patients after prior drug exposure. The expression of histone lysine demethylase genes (KDMs) was increased in TMZ-R cells compared to parental cells, and TMZ resistance or restored sensitivity was mimicked by over-expressing or inactivating KDM5A. Methylation and expression of O6-methylguanine-DNA methyltransferase (MGMT) and drug efflux mechanisms were not altered in TMZ-R cells compared to parental TMZ sensitive cells. TMZ-R cells transiently acquired morphologic and molecular characteristics of differentiated tumor cells, features that were lost after drug wash-out. In conclusion, we demonstrated that treatment-induced TMZ resistance in GBM involves epigenetic mechanisms in a subset of slow-cycling and transiently partially differentiated cells that escape drug cytotoxicity, overcome G2 checkpoint and sustain clonal growth. We found that TMZ-R cells are sensitive to histone deacethylase inhibitors (HDACi) that synergize with TMZ. This strong synergism could be exploited to develop novel combined adjuvant therapies for this rapidly progressing and invariably lethal cancer.