ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma
ATRX/EZH2 complex epigenetically regulates FADD/PARP1 axis, contributing to TMZ resistance in glioma
复制标题
ATRX/EZH2 复合物表观遗传调节 FADD/PARP1 轴，导致神经胶质瘤中 TMZ 耐药
DOI：
10.7150/thno.41219
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Jiang, Tao
中科院分区：
文献类型：
--
作者：
Han, Bo;Meng, Xiangqi;Jiang, Tao
原理：胶质瘤是成人中最常见的原发性恶性脑肿瘤。替莫唑胺（TMZ）作为一线化疗药物，其耐药性是胶质瘤治疗中的一个主要问题。α地中海贫血/智力低下综合征X连锁（ATRX）基因的改变是胶质瘤中最常见的遗传异常之一。因此，迫切需要阐明ATRX在胶质瘤TMZ耐药中的作用。方法：我们对基因表达、DNA甲基化谱以及RNA和ChIP-seq数据集进行了生物信息学分析。CRISPR-Cas9基因编辑系统用于在TMZ抗性细胞中实现ATRX敲除。通过体内外实验研究ATRX在胶质瘤TMZ耐药中的作用。结果如下：我们发现ATRX表达通过STAT 5 b/TET 2复合物介导的DNA去甲基化上调，并通过稳定TMZ耐药细胞中的PARP 1蛋白来加强DNA损伤修复。ATRX通过经由H3 K27 me 3富集下调FADD表达而引起PARP 1稳定，这在TMZ抗性细胞中依赖于ATRX/EZH 2复合物。磁共振成像（MRI）显示，PARP抑制剂与TMZ一起抑制ATRX野生型TMZ耐药颅内异种移植模型中的胶质瘤生长。结论：本研究进一步阐明了ATRX/PARP 1轴参与TMZ耐药的新机制。我们的结果提供了大量的新证据，PARP抑制剂可能是一个潜在的辅助剂，在克服ATRX介导的TMZ耐药胶质瘤。
Rationale: Glioma is the most common primary malignant brain tumor in adults. Chemoresistance of temozolomide (TMZ), the first-line chemotherapeutic agent, is a major issue in the management of patients with glioma. Alterations of alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene constitute one of the most prevalent genetic abnormalities in gliomas. Therefore, elucidation of the role of ATRX contributing to TMZ resistance in glioma is urgently needed. Methods: We performed the bioinformatics analysis of gene expression, and DNA methylation profiling, as well as RNA and ChIP-seq data sets. CRISPR-Cas9 gene editing system was used to achieve the ATRX knockout in TMZ resistant cells. In vitro and in vivo experiments were carried out to investigate the role of ATRX contributing to TMZ resistance in glioma. Results: We found that ATRX expression was upregulated via DNA demethylation mediated by STAT5b/TET2 complex and strengthened DNA damage repair by stabilizing PARP1 protein in TMZ resistant cells. ATRX elicited PARP1 stabilization by the down-regulating of FADD expression via the H3K27me3 enrichment, which was dependent on ATRX/EZH2 complex in TMZ resistant cells. Magnetic resonance imaging (MRI) revealed that the PARP inhibitor together with TMZ inhibited glioma growth in ATRX wild type TMZ resistant intracranial xenograft models. Conclusions: The present study further illustrated the novel mechanism of the ATRX/PARP1 axis contributing to TMZ resistance. Our results provided substantial new evidence that PARP inhibitor might be a potential adjuvant agent in overcoming ATRX mediated TMZ resistance in glioma.