SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B.
复制标题
SIX3 是一种肿瘤抑制因子，通过 AURKA/B 的转录抑制来抑制星形细胞瘤的肿瘤发生
DOI：
10.1186/s13045-017-0483-2
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发表时间：
2017-06-08
影响因子：
28.5
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Yu Z;Sun Y;She X;Wang Z;Chen S;Deng Z;Zhang Y;Liu Q;Liu Q;Zhao C;Li P;Liu C;Feng J;Fu H;Li G;Wu M
SIX同源框3（SIX 3）是眼正弦同源框转录因子家族的成员。它在神经系统发育中起着至关重要的作用。我们的前期研究表明SIX 3基因在星形细胞瘤中高甲基化，表达降低，但SIX 3的作用尚不清楚。染色质免疫沉淀（ChIP）和荧光素酶报告基因分析用于证实SIX 3与极光激酶A（AURKA）和极光激酶B（AURKB）的启动子区的结合。共聚焦成像和免疫共沉淀（Co-IP）用于检测AURKA和AURKB之间的相互作用。进行流式细胞术以评估SIX 3对细胞周期分布的影响。进行集落形成、EdU掺入、transwell和颅内异种移植物测定以证明SIX 3对星形细胞瘤细胞的恶性表型的影响。SIX 3被鉴定为AURKA和AURKB的新型负转录调节因子，并且其在星形细胞瘤细胞中以剂量依赖性方式降低AURKA和AURKB的表达。重要的是，AURKA和AURKB之间的相互作用稳定并保护AURKA/B免于降解，并且SIX 3的过表达不影响这些相互作用; SIX 3还作为肿瘤抑制因子，并且其通过AURKA或AURKB的负调节在翻译后水平增加p53活性和表达，减少中心体数目畸变和染色体错配的事件，并且显著抑制增殖，星形细胞瘤在体内外的侵袭和成瘤性。此外，使用原代培养的星形细胞瘤细胞的实验表明，SIX 3和突变型p53低表达的星形细胞瘤患者对极光激酶抑制剂治疗更敏感。SIX 3是一种新的负性转录调节因子，在星形细胞瘤中作为肿瘤抑制因子直接抑制AURKA和AURKB的转录。首次发现AURKA和AURKB的功能相互作用，这有助于保护其稳定性，并部分解释了它们在癌症中持续高表达和活性。SIX 3是一种潜在的生物标志物，可用于预测星形细胞瘤患者对极光激酶抑制剂的反应。本文的在线版本（doi：10.1186/s13045-017-0483-2）包含补充材料，可供授权用户使用。
SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors. The online version of this article (doi:10.1186/s13045-017-0483-2) contains supplementary material, which is available to authorized users.