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Thyroid hormone receptor beta ( THRB ) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of  THRB  in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of  THRB  in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in  THRB  and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However,  THRB  CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples.  In silico  analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting  THRB  transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3′UTR of  THRB,  and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous  TRHB  by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of  THRB  transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased  THRB  expression in ccRCC. In contrast,  THRB  is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of  THRB  in ccRCC tumors.

Epigenetic Regulation of Thyroid Hormone Receptor Beta in Renal Cancer