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Loss of type III transforming growth factor-β receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma

Oncogene volume 29, pages 2905–2915 (2010)Cite this article

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Abstract

Loss of transforming growth factor-β receptor III (TβRIII) correlates with loss of transforming growth factor-β (TGF-β) responsiveness and suggests a role for dysregulated TGF-β signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TβRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TβRIII expression in human cells. We localize GATA3′s binding to a 10-bp region of the TβRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TβRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TβRIII expression during ccRCC progression.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ccRCC:

clear cell renal cell carcinoma

TβRIII:

type III transforming growth factor-β receptor

TGF-β:

transforming growth factor-β

TSA:

trichostatin A

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Acknowledgements

We thank Holly Hammond for her close editing of the manuscript. We also thank Tam How, Brandy Edenfield and Gregory Kennedy for their technical support. This work was funded in part by NIH Grant CA104505 (JAC and CGW), 3RO1CA104505-05S1 (JAC), Dr Ellis and Dona Brunton Rare Cancer Research Fund (JAC), NIH Grant CA106307 (GCB) and a generous gift from Susan A Olde, OBE.

Author information

Author notes

  1. H Zou

    Present address: 7Current address: EXACT Sciences Corporation, 505 S. Rosa Road, Madison, WI 53719, USA.,

  2. N Hempel

    Present address: 8Current address: Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, MC-151, Albany, NY, USA.,

Authors and Affiliations

  1. Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL, USA

    S J Cooper, S N LeGrand, L A Marlow, C A von Roemeling, D C Radisky & J A Copland

  2. Department of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA

    H Zou

  3. Department of Pathology, Mayo Clinic, Jacksonville, FL, USA

    K J Wu

  4. Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    N Hempel & G C Blobe

  5. Department of Urology, University of Texas MD Anderson Cancer Center Houston, Houston, TX, USA

    V Margulis & C G Wood

  6. Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA

    H W Tun

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  1. S J Cooper
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Correspondence to J A Copland.

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Cooper, S., Zou, H., LeGrand, S. et al. Loss of type III transforming growth factor-β receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma. Oncogene 29, 2905–2915 (2010). https://doi.org/10.1038/onc.2010.64

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