Abstract
G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. Gα12 and Gα13, encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene and are implicated in tumor progression. However, the molecular mechanisms by which Gα12/13 activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of Gα12/13 in human ovarian cancer tissues. Gα12/13 activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, Gα12/13 activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that Gα12/13 promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siegel R, Ma J, Zou Z, Jemal A . Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9–29.
Dorsam RT, Gutkind JS . G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7: 79–94.
Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 2010; 466: 869–873.
Xu N, Bradley L, Ambdukar I, Gutkind JS . A mutant alpha subunit of G12 potentiates the eicosanoid pathway and is highly oncogenic in NIH 3T3 cells. Proc Natl Acad Sci USA 1993; 90: 6741–6745.
Xu N, Voyno-Yasenetskaya T, Gutkind JS . Potent transforming activity of the G13 alpha subunit defines a novel family of oncogenes. Biochem Biophys Res Commun 1994; 201: 603–609.
Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y et al. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci USA 2006; 103: 8173–8178.
Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ . A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem 2006; 281: 26483–26490.
Yagi H, Tan W, Dillenburg-Pilla P, Armando S, Amornphimoltham P, Simaan M et al. A synthetic biology approach reveals a CXCR4-G13-Rho signaling axis driving transendothelial migration of metastatic breast cancer cells. Sci Signal 2011; 4: ra60.
Gan CP, Patel V, Mikelis CM, Zain RB, Molinolo AA, Abraham MT et al. Heterotrimeric G-protein alpha-12 (Galpha12) subunit promotes oral cancer metastasis. Oncotarget 2014; 5: 9626–9640.
Worzfeld T, Wettschureck N, Offermanns S . G(12)/G(13)-mediated signalling in mammalian physiology and disease. Trends Pharmacol Sci 2008; 29: 582–589.
Pan D . The hippo signaling pathway in development and cancer. Dev Cell 2010; 19: 491–505.
Ramos A, Camargo FD . The Hippo signaling pathway and stem cell biology. Trends Cell Biol 2012; 22: 339–346.
Zhao B, Li L, Lei Q, Guan KL . The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 2010; 24: 862–874.
Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Cur Biol CB 2007; 17: 2054–2060.
Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007; 130: 1120–1133.
Johnson R, Halder G . The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov 2014; 13: 63–79.
Harvey KF, Zhang X, Thomas DM . The Hippo pathway and human cancer. Nat Rev Cancer 2013; 13: 246–257.
Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X . Overexpression of Yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 2010; 101: 1279–1285.
Steinhardt AA, Gayyed MF, Klein AP, Dong J, Maitra A, Pan D et al. Expression of Yes-associated protein in common solid tumors. Hum Pathol 2008; 39: 1582–1589.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125: 1253–1267.
Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007; 21: 2747–2761.
Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 2012; 150: 780–791.
Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014; 25: 831–845.
Fukuhara S, Chikumi H, Gutkind JS . RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? Oncogene 2001; 20: 1661–1668.
Kuilman T, Michaloglou C, Mooi WJ, Peeper DS . The essence of senescence. Genes Dev 2010; 24: 2463–2479.
Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH . The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 2005; 24: 2076–2086.
Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 2012; 26: 1300–1305.
O'Hayre M, Vazquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer 2013; 13: 412–424.
Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 2015; 21: 938–945.
Muppidi JR, Schmitz R, Green JA, Xiao W, Larsen AB, Braun SE et al. Loss of signalling via Galpha13 in germinal centre B-cell-derived lymphoma. Nature 2014; 516: 254–258.
Chan AM, Fleming TP, McGovern ES, Chedid M, Miki T, Aaronson SA . Expression cDNA cloning of a transforming gene encoding the wild-type G alpha 12 gene product. Mol Cell Biol 1993; 13: 762–768.
Goldsmith ZG, Ha JH, Jayaraman M, Dhanasekaran DN . Lysophosphatidic acid stimulates the proliferation of ovarian cancer cells via the gep proto-oncogene Galpha(12). Genes Cancer 2011; 2: 563–575.
Yang YM, Lee WH, Lee CG, An J, Kim ES, Kim SH et al. Gα12 gep oncogene deregulation of p53-responsive microRNAs promotes epithelial-mesenchymal transition of hepatocellular carcinoma. Oncogene 2015; 34: 2910–2922.
Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 2011; 144: 782–795.
Chan EH, Nousianen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH . The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 2005; 24: 2076–2086.
Miller E, Yang J, DeRan M, Wu C, Su AI, Bonamy GM et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem Biol 2012; 19: 955–962.
Mo JS, Yu FX, Gong R, Brown JH, Guan KL . Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev 2012; 26: 2138–2143.
Sudol M, Shields DC, Farooq A . Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Semin Cell Dev Biol 2012; 23: 827–833.
Rosenbaum DM, Rasmussen SG, Kobilka BK . The structure and function of G-protein-coupled receptors. Nature 2009; 459: 356–363.
Galandrin S, Oligny-Longpre G, Bouvier M . The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol Sci 2007; 28: 423–430.
Rajagopal S, Rajagopal K, Lefkowitz RJ . Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 2010; 9: 373–386.
Yotsumoto F, Yagi H, Suzuki SO, Oki E, Tsujioka H, Hachisuga T et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun 2008; 365: 555–561.
Itamochi H, Kato M, Nishimura M, Oumi N, Oishi T, Shimada M et al. Establishment and characterization of a novel ovarian clear cell adenocarcinoma cell line, TU-OC-1, with a mutation in the PIK3CA gene. Hum Cell 2013; 26: 121–127.
Imai S, Kiyozuka Y, Maeda H, Noda T, Hosick HL . Establishment and characterization of a human ovarian serous cystadenocarcinoma cell line that produces the tumor markers CA-125 and tissue polypeptide antigen. Oncology 1990; 47: 177–184.
Tan W, Martin D, Gutkind JS . The Galpha13-Rho signaling axis is required for SDF-1-induced migration through CXCR4. J Biol Chem 2006; 281: 39542–39549.
Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS . Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 2004; 64: 5212–5224.
Acknowledgements
We are grateful to Ms Emiko Hori, Ms Yoko Miyanari and Research Support Center, Graduate School of Medical Science, Kyushu University for technical supports. This study was supported in part by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#24791709 and #26861332).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Yagi, H., Asanoma, K., Ohgami, T. et al. GEP oncogene promotes cell proliferation through YAP activation in ovarian cancer. Oncogene 35, 4471–4480 (2016). https://doi.org/10.1038/onc.2015.505
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2015.505
This article is cited by
-
The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors
Oncogene (2022)
-
GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
Cell Death & Disease (2021)
-
β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer
Nature Communications (2019)
-
PTEN lipid phosphatase inactivation links the hippo and PI3K/Akt pathways to induce gastric tumorigenesis
Journal of Experimental & Clinical Cancer Research (2018)
-
Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions
Journal of Experimental & Clinical Cancer Research (2018)