PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity.
PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity.
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DOI：
10.18632/oncotarget.11273
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发表时间：
2016-09-20
期刊：
影响因子：
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通讯作者：
Mansukhani A
中科院分区：
文献类型：
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作者：
Basu-Roy U;Han E;Rattanakorn K;Gadi A;Verma N;Maurizi G;Gunaratne PH;Coarfa C;Kennedy OD;Garabedian MJ;Basilico C;Mansukhani A
骨肉瘤（Osteosarcoma， OS）是一种高度侵袭性的儿童骨癌，大多数肿瘤细胞仍未成熟，不能分化成成骨细胞。然而，OS细胞容易对脂肪生成刺激作出反应，这表明它们保留了间充质干细胞样特性。在这里，我们证明核受体PPARγ激动剂如抗糖尿病、噻唑烷二酮（TZD）药物在人类、小鼠和犬OS细胞以及小鼠肿瘤中诱导生长停滞并导致脂肪分化。基因表达分析显示，TZDs诱导脂质代谢通路，同时抑制Hippo-YAP通路、Wnt信号通路和癌症相关增殖通路的靶点。值得注意的是，TZD的作用似乎仅限于高Sox2表达的癌症干细胞群体，并且依赖于PPARγ的表达。TZDs还通过引起致瘤性所需的转录因子SOX2和YAP的细胞质隔离来影响生长和细胞命运。最后，我们确定了一个基于Wnt/Hippo靶基因和PPARγ的tzd调控基因特征，该特征可以预测患者的预后。总之，这项工作强调了PPARγ激动剂在诱导脂肪形成和模拟肿瘤抑制hippo通路之间的新联系。这也说明了以tzd为基础的骨肉瘤分化治疗药物再利用的潜力。
Osteosarcoma (OS) is a highly aggressive pediatric bone cancer in which most tumor cells remain immature and fail to differentiate into bone-forming osteoblasts. However, OS cells readily respond to adipogenic stimuli suggesting they retain mesenchymal stem cell-like properties. Here we demonstrate that nuclear receptor PPARγ agonists such as the anti-diabetic, thiazolidinedione (TZD) drugs induce growth arrest and cause adipogenic differentiation in human, mouse and canine OS cells as well as in tumors in mice. Gene expression analysis reveals that TZDs induce lipid metabolism pathways while suppressing targets of the Hippo-YAP pathway, Wnt signaling and cancer-related proliferation pathways. Significantly, TZD action appears to be restricted to the high Sox2 expressing cancer stem cell population and is dependent on PPARγ expression. TZDs also affect growth and cell fate by causing the cytoplasmic sequestration of the transcription factors SOX2 and YAP that are required for tumorigenicity. Finally, we identify a TZD-regulated gene signature based on Wnt/Hippo target genes and PPARγ that predicts patient outcomes. Together, this work highlights a novel connection between PPARγ agonist in inducing adipogenesis and mimicking the tumor suppressive hippo pathway. It also illustrates the potential of drug repurposing for TZD-based differentiation therapy for osteosarcoma.