Ascl2 activation by YAP1/KLF5 ensures the self-renewability of colon cancer progenitor cells.
Ascl2 activation by YAP1/KLF5 ensures the self-renewability of colon cancer progenitor cells.
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YAP1/KLF5 激活 Ascl2 确保结肠癌祖细胞的自我更新能力
DOI：
10.18632/oncotarget.22673
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发表时间：
2017-12-12
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Wei X;Ye J;Shang Y;Chen H;Liu S;Liu L;Wang R
Achaete scute-like 2（Ascl 2）是Wnt信号传导的靶点，其通过其他信号传导的调节是不确定的。现在，我们证明了来自HT-29或Caco-2细胞的CD 133 +/CD 44+细胞群具有癌症干细胞（CSC）特性，其具有高表达的Ascl 2，其与Hippo信号通路相关。YAP 1对CD 133 +/CD 44 + HT-29或Caco-2细胞的干扰降低了它们的增殖、集落形成能力和体外肿瘤球形成，并抑制了“干性”相关基因和Ascl 2表达。在HT-29或Caco-2细胞中强制YAP 1表达引发了相反的变化。Ascl 2干扰逆转了YAP 1强制表达的HT-29或Caco-2细胞的表型。Krüppel样因子5（KLF 5）蛋白，而不是KLF 5 mRNA水平，由于YAP 1过表达而增加，据报道YAP 1过表达可阻止KLF 5降解。免疫共沉淀（Co-IP）实验表明YAP 1与HT-29和Caco-2细胞中的KLF 5结合。荧光素酶和染色质免疫沉淀（ChIP）分析表明，YAP 1和KLF 5均与Ascl 2启动子中GC盒的前两个位点结合，并诱导Ascl 2的转录。通过YAP 1干扰降低Ascl 2转录需要Ascl 2启动子内的完整KLF 5结合位点（GC盒），KLF 5敲低降低YAP 1结合和YAP 1过表达后的Ascl 2荧光素酶报告基因活性。在结直肠癌（CRC）样品中观察到YAP 1和Ascl 2 mRNA水平之间正相关。因此，我们的研究表明，大肠癌祖细胞的命运决定者Ascl 2可以被大肠癌祖细胞中的Hippo信号通路激活，并确保其自我更新能力。
Achaete scute-like 2 (Ascl2) is the Wnt signaling target, its regulation by other signaling is undefined. Now we demonstrated that CD133+/CD44+ cell population from HT-29 or Caco-2 cells exhibited cancer stem cell (CSC) properties with highly expressed Ascl2, which is related to the Hippo signaling pathway. YAP1 interference in CD133+/CD44+ HT-29 or Caco-2 cells reduced their proliferation, colony-forming ability and tumorsphere formation in vitro and inhibited the ‘stemness’-associated genes and Ascl2 expression. Enforcing YAP1 expression in HT-29 or Caco-2 cells triggered the opposite changes. Ascl2 interference reversed the phenotype of YAP1-enforced expressed HT-29 or Caco-2 cells. Krüppel-like factor 5 (KLF5) protein, not KLF5 mRNA levels, were increased due to YAP1 overexpression which is reported to prevent KLF5 degradation. Co-immunoprecipitation (Co-IP) assays demonstrated that YAP1 bound with KLF5 in HT-29 and Caco-2 cells. Luciferase and chromatin immunoprecipitation (ChIP) assays indicated that both YAP1 and KLF5 bound to the first two loci with GC-boxes in Ascl2 promoter and induced Ascl2 transcription. The decreased Ascl2 transcription by YAP1 interference required an intact KLF5 binding site (GC-box) within Ascl2 promoter, KLF5 knockdown reduced YAP1 binding and Ascl2 luciferase reporter activity upon YAP1 overexpression. Positive correlation among YAP1 and Ascl2 mRNA levels was observed in colorectal cancer (CRC) samples. Thus, our study demonstrated that Ascl2, a fate decider of CRC progenitor cells can be activated by the Hippo signaling pathway in CRC progenitor cells, and ensured their self-renewability.
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影响因子：
5.4
作者：
Katoh M;Katoh M
通讯作者：
Katoh M
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影响因子：
3.7
作者：
Du X;Dong Y;Shi H;Li J;Kong S;Shi D;Sun LV;Xu T;Deng K;Tao W
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影响因子：
64.8
作者：
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通讯作者：
Wrana, Jeffrey L.
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
13.6
作者：
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通讯作者：
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