Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China.
Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Chinese Glioma Cooperative Group (CGCG), Beijing 100050, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China.
Cancer Lett. 2018 Apr 10;419:280-290. doi: 10.1016/j.canlet.2018.01.056. Epub 2018 Jan 31.
Mutations in ATRX constitute the most prevalent genetic abnormalities in gliomas. The presence of ATRX mutations in glioma serves as a marker of better prognosis with longer patient survival although the underlying mechanisms are poorly understood. In the present study, we found that ATRX biological function was significantly involved in DNA replication and repair. CRISPR/Cas9-mediated genetic inactivation of ATRX induced inhibition of cell proliferation, invasion and vasculogenic mimicry. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in ATRX knockout glioma cells. Moreover, we confirmed that ATRX knockout resulted in a failure to trigger ATM phosphorylation and finally restrained the activation of downstream proteins of the ATM pathway. The ATM-associated DNA repair pathway was extensively compromised in ATRX knockout cells owing to decreased histone H3K9me3 availability. Public databases also showed that patients with low ATRX expression exhibited preferable overall survival and profited more from TMZ treatment. These data suggest that ATRX is involved in DNA damage repair by regulating the ATM pathway and might serve as a prognostic maker in predicting TMZ chemosensitivity.
在神经胶质瘤中， ATRX 突变是最常见的遗传异常。尽管其潜在机制尚不清楚，但存在 ATRX 突变的神经胶质瘤是预后较好、患者生存期较长的标志物。在本研究中，我们发现 ATRX 的生物学功能与 DNA 复制和修复显著相关。CRISPR/Cas9 介导的 ATRX 基因失活诱导细胞增殖、侵袭和血管生成拟态抑制。此外，替莫唑胺（TMZ ）处理诱导 ATRX 敲除神经胶质瘤细胞产生更大的 DNA 损伤和凋亡变化。此外，我们证实 ATRX 敲除导致 ATM 磷酸化无法被触发，最终抑制了 ATM 通路下游蛋白的激活。由于组蛋白 H3K9me3 的可用性降低，ATR X 敲除细胞中 ATM 相关的 DNA 修复途径受到广泛破坏。公共数据库还显示， ATRX 表达水平低的患者具有更好的总生存期，并从 TMZ 治疗中获益更多。这些数据表明， ATRX 通过调节 ATM 通路参与 DNA 损伤修复，可能作为预测 TMZ 化疗敏感性的预后标志物。
