RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling

Li Yang; Liu Min; Yang ShutingFuller Ashley M.Karin Eisinger-Mathason T. S.Yang Shuying

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RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling

机译：RGS12 是一种新型的骨肉瘤肿瘤抑制因子，可抑制 YAP-TEAD1-Ezrin 信号传导

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Osteosarcoma (OS) is the most common primary malignancy of the bone that predominantly affects children and adolescents. Hippo pathway is a crucial regulator of organ size and tumorigenesis. However, how Hippo pathway regulates the occurrence of osteosarcoma is largely unknown. Here, we reported the regulator of G protein signaling protein 12 (RGS12) is a novel Hippo pathway regulator and tumor suppressor of osteosarcoma. Depletion of Rgs12 promotes osteosarcoma progression and lung metastasis in an orthotopic xenograft mouse model. Our data showed that the knockdown of RGS12 upregulates Ezrin expression through promoting the GNA12/13-RhoA-YAP pathway. Moreover, RGS12 negatively regulates the transcriptional activity of YAP/TEAD1 complex through its PDZ domain function to inhibit the expression and function of the osteosarcoma marker Ezrin. PDZ domain peptides of RGS12 can inhibit the development of intratibial tumor and lung metastases. Collectively, this study identifies that the RGS12 is a novel tumor suppressor in osteosarcoma through inhibiting YAP-TEAD1-Ezrin signaling pathway and provides a proof of principle that targeting RGS12 may be a therapeutic strategy for osteosarcoma.

机译：骨肉瘤（OS）是最常见的原发性骨恶性肿瘤，主要影响儿童和青少年。Hippo通路是器官大小和肿瘤发生的关键调节因子。然而，Hippo 通路如何调节骨肉瘤的发生在很大程度上是未知的。在这里，我们报道了G蛋白信号转导蛋白12（RGS12）的调节因子是一种新型的Hippo通路调节因子和骨肉瘤的肿瘤抑制因子。Rgs12 的耗竭促进原位异种移植小鼠模型中的骨肉瘤进展和肺转移。我们的数据显示，RGS12 的敲低通过促进 GNA12/13-RhoA-YAP 通路上调 Ezrin 表达。此外，RGS12 通过其 PDZ 结构域功能负调控 YAP/TEAD1 复合物的转录活性，从而抑制骨肉瘤标志物 Ezrin 的表达和功能。RGS12的PDZ结构域肽可以抑制胫骨内肿瘤和肺转移的发展。总的来说，本研究通过抑制 YAP-TEAD1-Ezrin 信号通路确定了 RGS12 是骨肉瘤中的一种新型肿瘤抑制因子，并提供了靶向 RGS12 可能是骨肉瘤治疗策略的原理证明。

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《Oncogene》 |2021年第14期|2553-2566|共14页
作者
Li Yang; Liu Min; Yang ShutingFuller Ashley M.Karin Eisinger-Mathason T. S.Yang Shuying;
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Univ Penn, Sch Dent Med, Dept Basic & Translat Sci, Philadelphia, PA 19104 USA;

Univ Penn, Abramson Family Canc Res Inst, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA;

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正文语种英语
中图分类肿瘤学;
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RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling

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