Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences of Tianjin Medical University, Tianjin, China.
Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Neuro Oncol. 2019 Jun 10;21(6):742-754. doi: 10.1093/neuonc/noz038.
Upregulation of staphylococcal nuclease domain-containing protein 1 (SND1) is a common phenomenon in different human malignant tissues. However, little information is available on the underlying mechanisms through which SND1 affects glioma cell proliferation and invasion.
SND1, Ras homolog family member A (RhoA), and marker of proliferation Ki-67 (MKI67) were analyzed in 187 gliomas by immunostaining. The correlation between those markers and patients' prognoses was assessed using the Kaplan-Meier estimator. Gene Ontology, chromatin immunoprecipitation, electrophoretic mobility shift assay, and chromosome conformation capture were applied to identify SND1-activated target genes. We also used MTT, colony formation, transwell and orthotopic implantation assays to investigate SND1 function in glioma cell proliferative and invasive activity.
We identified SND1 and RhoA as independent predictors of poor prognosis in glioma patients. SND1 knockdown significantly suppressed the proliferation and invasion of glioma cells. Mechanistically, we discovered that SND1 facilitated malignant glioma phenotypes by epigenetically inducing chromatin topological interaction, which activated downstream RhoA transcription. RhoA sequentially regulated expression of CCND1, CCNE1, CDK4, and CDKN1B and accelerated G1/S phase transition in glioma cell proliferation.
Our findings identify SND1 as a novel chromatin architectural modifier and promising prognostic indicator for glioma classification and treatment.
葡萄球菌核酸酶结构域蛋白 1（SND1）的上调是不同人类恶性组织中的常见现象。然而，关于 SND1 影响神经胶质瘤细胞增殖和侵袭的潜在机制的信息很少。
通过免疫染色分析了 187 例神经胶质瘤中的 SND1、Ras 同源家族成员 A（RhoA）和增殖标志物 Ki-67（MKI67）。使用 Kaplan-Meier 估计器评估这些标志物与患者预后之间的相关性。应用基因本体论、染色质免疫沉淀、电泳迁移率变动分析和染色体构象捕获来鉴定 SND1 激活的靶基因。我们还使用 MTT、集落形成、Transwell 和原位植入测定来研究 SND1 在神经胶质瘤细胞增殖和侵袭活性中的功能。
我们确定 SND1 和 RhoA 是神经胶质瘤患者预后不良的独立预测因子。SND1 敲低显著抑制了神经胶质瘤细胞的增殖和侵袭。从机制上讲，我们发现 SND1 通过表观遗传诱导染色质拓扑相互作用促进恶性神经胶质瘤表型，从而激活下游 RhoA 转录。RhoA 依次调节 CCND1、CCNE1、CDK4 和 CDKN1B 的表达，并加速神经胶质瘤细胞增殖中的 G1/S 期转变。
我们的研究结果确定 SND1 为一种新型染色质结构修饰因子，是神经胶质瘤分类和治疗的有前途的预后指标。
