HMGB1 contributes to SASH1 methylation to attenuate astrocyte adhesion
HMGB1 contributes to SASH1 methylation to attenuate astrocyte adhesion
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DOI：
10.1038/s41419-019-1645-7
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发表时间：
2019-05-28
影响因子：
9
通讯作者：
Yang, Liu
中科院分区：
文献类型：
--
作者：
Wu, Ronghua;Yan, Yingying;Yang, Liu
SAM 和 SH3 结构域包含 1 (SASH1) 是一种支架蛋白，被认为是一种肿瘤抑制因子。最近的研究证实了SASH1在许多肿瘤中的表达降低。我们前期的临床研究发现SASH1在正常脑组织中广泛表达，但在胶质瘤组织中表达减少或缺失。然而，SASH1在正常星形胶质细胞中的功能以及神经胶质瘤组织中SASH1水平降低的原因尚不清楚。在这项研究中，我们发现在星形胶质细胞中，SASH1 在细胞粘附中发挥作用。我们观察到，培养的星形胶质细胞中 SASH1 表达的敲低显着降低了细胞粘附并增加了侵袭。相反，C6细胞中SASH1的过度表达显着促进细胞粘附并减少细胞侵袭。此外，我们发现整合素家族的一个成员整合素β8的表达水平在SASH1下调的星形胶质细胞中显着降低，而在SASH1上调的C6细胞中表达水平显着升高。此外，甲基化和ChIP检测结果表明，C6细胞中SASH1基因的甲基化水平明显高于星形胶质细胞，并且HMGB1可以与SASH1基因的CpG岛结合。星形胶质细胞中 HMGB1 过表达显着增加了 SASH1 基因的甲基化水平。这项研究首次揭示了HMGB1有助于SASH1基因的甲基化，我们的研究结果表明甲基化下调了SASH1基因的表达，随后降低了整合素β8的表达，从而减少细胞粘附并促进细胞迁移。
SAM and SH3 domain-containing 1 (SASH1), a scaffold protein, is regarded as a tumor suppressor. Recent studies have verified the decreased expression of SASH1 in many tumors. Our previous clinical investigation found that SASH1 was widely expressed in normal brain tissues but reduced or absent in glioma tissues. However, the functions of SASH1 in normal astrocytes and the reasons for the reductions in SASH1 levels in glioma tissues are unclear. In this study, we found that in astrocytes, SASH1 functions in cell adhesion. We observed that knockdown of SASH1 expression in cultured astrocytes significantly decreased cell adhesion and increased invasion. Conversely, overexpression of SASH1 in C6 cells markedly promoted cell adhesion and decreased cell invasion. In addition, we found that the expression level of one member of the integrin family, integrin beta 8, was significantly reduced in SASH1-downregulated astrocytes and elevated in SASH1-upregulated C6 cells. Furthermore, the results of methylation and ChIP assays showed that the methylation level of the SASH1 gene was markedly higher in C6 cells than in astrocytes and that HMGB1 could bind to the CpG islands of the SASH1 gene. HMGB1 overexpression in astrocytes significantly increased the methylation level of the SASH1 gene. This study reveals, for the first time, that HMGB1 contributes to the methylation of the SASH1 gene, and our findings suggest that methylation downregulates the expression of the SASH1 gene and later reduces integrin beta 8 expression, thereby reducing cell adhesion and promoting cell migration.