Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth
Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth
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DOI：
10.1158/1541-7786.mcr-17-0382
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发表时间：
2018-02-01
影响因子：
5.2
通讯作者：
Hata, Yutaka
中科院分区：
文献类型：
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作者：
Maruyama, Junichi;Inami, Kazutoshi;Hata, Yutaka
yes相关蛋白1 （YAP1）与许多转录因子相互作用，包括tea结构域家族蛋白（TEAD）和p73。YAP1受肿瘤抑制因子Hippo通路的负调控。在人类癌症中，Hippo通路的失调和YAP1基因扩增导致YAP1的激活，从而诱导上皮-间质转化（EMT）和耐药。YAP1抑制剂有望在癌症治疗中发挥作用。另一方面，在某些癌症中，YAP1上调p73依赖基因的转录，并作为肿瘤抑制因子。此外，由于YAP1调节组织干细胞的自我更新和分化，并在组织稳态中发挥重要作用，YAP1激活物可能有助于再生医学。考虑到这一点，我们使用在YAP1共表达下表达tead应答荧光报告基因的人视网膜色素上皮ARPE-19细胞筛选YAP1激活因子。从广泛的化合物文库（n = 18,606）中鉴定出47个候选YAP1激活剂。对这些化合物进行了表征，以确定该试验是否提供了真正的YAP1激活剂。重要的是，一种YAP1激活剂对人类多发性骨髓瘤IM-9细胞和慢性髓系白血病K562细胞有效。意义：YAP1激活限制生长，诱导细胞凋亡，并可能对抑制血液学癌症有用。
Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial-mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n = 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells.Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers.