RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling
- 8 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (14), 2553-2566
- https://doi.org/10.1038/s41388-020-01599-z
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR061052)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG048388)
This publication has 57 references indexed in Scilit:
- The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domainProceedings of the National Academy of Sciences of the United States of America, 2012
- Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in miceJournal of Bone and Mineral Research, 2011
- AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinomaOncogene, 2010
- PDZ domains and their binding partners: structure, specificity, and modificationCell Communication and Signaling, 2010
- The Hippo–YAP pathway: new connections between regulation of organ size and cancerCurrent Opinion in Cell Biology, 2008
- Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheresBMC Cancer, 2008
- Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineageProceedings of the National Academy of Sciences of the United States of America, 2008
- Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human diseaseGenes & Development, 2008
- Identification of Tumorsphere- and Tumor-Initiating Cells in HER2/Neu-Induced Mammary TumorsCancer Research, 2007
- RGS12 Is Essential for RANKL-Evoked Signaling for Terminal Differentiation of Osteoclasts In VitroJournal of Bone and Mineral Research, 2007