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

Oncogene volume 40, pages 2553–2566 (2021)Cite this article

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Abstract

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.

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Fig. 1: RGS12 is downregulated in both human and mouse osteosarcoma tissues.
Fig. 2: RGS12 inhibits osteosarcoma cell migration, invasion, and tumorsphere formation in vitro.
Fig. 3: Knockdown of RGS12 in SaOS2 promotes intratibial primary tumor growth and lung metastasis in SCID mice.
Fig. 4: RGS12 inhibits transcriptional YAP/TEAD1 activity through its PDZ domain function.
Fig. 5: Knockdown of RGS12 induces YAP-dependent Ezrin expression.
Fig. 6: RGS12 negatively regulates Ezrin expression via GNA12/13-RhoA-YAP pathway.
Fig. 7: RGS12 PDZ peptides inhibit osteosarcoma formation and lung metastasis.
Fig. 8: A proposed model to illustrate the regulatory mechanism of RGS12 on Ezrin expression in osteosarcoma.

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Acknowledgements

This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS, AR061052), the National Institute on Aging (NIA, AG048388) awarded to SY.

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Authors and Affiliations

  1. Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Yang Li, Min Liu, Shuting Yang & Shuying Yang

  2. The Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Ashley M. Fuller & T. S. Karin Eisinger-Mathason

  3. Center for Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Shuying Yang

  4. The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Shuying Yang

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SY-Y and YL conceived this study, generated hypotheses, and designed the experiments. YL, ML, ST-Y, AMF, and TSKE performed the experiments and analyzed the data. SY-Y and YL wrote, reviewed, and edited the paper. SY-Y supervised the project.

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Correspondence to Shuying Yang.

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Li, Y., Liu, M., Yang, S. et al. RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling. Oncogene 40, 2553–2566 (2021). https://doi.org/10.1038/s41388-020-01599-z

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