Transcriptional repressor GATA binding 1-mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation
Transcriptional repressor GATA binding 1-mediated repression of SRY-box 2 expression suppresses cancer stem cell functions and tumor initiation
复制标题
转录抑制因子 GATA 结合 1 介导的 SRY-box 2 表达抑制可抑制癌症干细胞功能和肿瘤发生。
DOI：
10.1074/jbc.ra118.003983
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发表时间：
2018-11-30
影响因子：
4.8
通讯作者：
Chen, Liming
中科院分区：
文献类型：
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作者：
Gong, Xue;Liu, Weiguang;Chen, Liming
癌症干细胞（CSC）已被报道存在于多种癌症中。SRY-box 2（SOX 2）是SOX家族转录因子的一员，在维持肿瘤干细胞的功能和促进肿瘤发生中起重要作用。然而，CSCs中SOX 2基因转录调控的潜在机制尚不清楚。在这项研究中，使用计算机模拟和实验方法，我们确定了转录抑制因子加塔结合1（TRPS 1），一种非典型的GATA型转录因子，作为一个重要的转录调节因子，抑制SOX 2的表达，从而抑制癌症的干性和肿瘤发生。从机制上讲，TRPS 1通过直接靶向SOX 2启动子中的共有GATA结合元件来抑制SOX 2表达，如ChIP和荧光素酶报告基因测定所阐明的。值得注意的是，在培养物中的体外乳腺球形成测定和在小鼠模型中的体内异种移植肿瘤起始实验揭示了TRPS 1介导的对SOX 2表达的抑制抑制CSC功能和肿瘤起始。总之，我们的研究提供了详细的机制洞察CSC功能和肿瘤启动的TRPS 1-SOX 2轴。
Cancer stem cells (CSCs) have been reported in a variety of cancers. SRY-box 2 (SOX2) is a member of the SOX family of transcription factors and has been shown to play a critical role in maintaining the functions of CSCs and promoting tumor initiation. However, the underlying mechanisms for the transcriptional regulation of the SOX2 gene in CSCs are unclear. In this study, using in silico and experimental approaches, we identified transcriptional repressor GATA binding 1 (TRPS1), an atypical GATA-type transcription factor, as a critical transcriptional regulator that represses SOX2 expression and thereby suppresses cancer stemness and tumorigenesis. Mechanistically, TRPS1 repressed SOX2 expression by directly targeting the consensus GATA-binding element in the SOX2 promoter as elucidated by ChIP and luciferase reporter assays. Of note, in vitro mammosphere formation assays in culture and in vivo xenograft tumor initiation experiments in mouse models revealed that TRPS1-mediated repression of SOX2 expression suppresses CSC functions and tumor initiation. Taken together, our study provides detailed mechanistic insights into CSC functions and tumor initiation by the TRPS1-SOX2 axis.