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

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.