Abstract
Inactivation of human SET domain containing protein 2 (SETD2) is a common event in clear cell renal cell carcinoma (ccRCC). However, the mechanism underlying loss of SETD2 function, particularly the post-transcriptional regulatory mechanism, still remains unclear. In the present study, we found that SETD2 was downregulated and inversely correlated with high expression of miR-106b-5p in ccRCC tissues and cell lines. Over-expression of miR-106b-5p resulted in the decreased mRNA and protein levels of SETD2 in ccRCC cells. In an SETD2 3'-UTR luciferase reporter system, miR-106b-5p downregulated the luciferase activity, and the effects were abolished by mutating the predicted miR-106b-5p binding site. Moreover, attenuation of miR-106b-5p induced cell cycle arrest at G0/G1 phase, suppressed cell proliferation, enhanced processing of caspase-3, and promoted cell apoptosis in ccRCC cells, whereas these effects were reversed upon knockdown of SETD2. In addition, transfection of miR-106b-5p antagomir resulted in the increased binding of H3K36me3 to the promoter of p53 and enhanced its activity, as well as upregulated the mRNA and protein levels of p53, and the effects were also abolished by cotransfection with si-SETD2. Collectively, our findings extend the knowledge about the regulation of SETD2 at the posttranscriptional level by miRNA and regulatory mechanism downstream of SETD2 in ccRCC.
Highlights
Sporadic clear cell renal cell carcinoma, the most common type of adult kidney cancer [1], is universally characterized by chromosome 3p deletions or loss of heterozygosity (LOH) on chromosome 3p [2]
Among the predicted miRNAs that might target SET domain containing protein 2 (SETD2), the expression of miR-23b-5p, miR-34b-3p, miR-106b-5p and miR-142–5p were significantly higher in clear cell renal cell carcinoma (ccRCC) cell lines and tissues, while miR-20a-5p showed no significant difference (Figure 1G)
Correlation analysis indicated that miR-23b-5p, miR-34b-3p and miR106b-5p were inversely correlated with the expression of SETD2 in ccRCC ( p < 0. 0001, Figure 1H)
Summary
Sporadic clear cell renal cell carcinoma (ccRCC), the most common type of adult kidney cancer [1], is universally characterized by chromosome 3p deletions or loss of heterozygosity (LOH) on chromosome 3p [2]. Loss of other tumor suppressor genes has shed additional light on this research topic [3, 14, 17,18,19,20], and the most recent studies suggest that dysfunction of tumor suppressor genes on 3p21, such as PBRM1, PTEN, BAP1, and SETD2, might play a vital role in both VHL-dependent or -independent cases [15, 18, 21, 22] These four tumor suppressor genes may act alone or cooperate with VHL inactivation to initiate tumor formation and/or promote progression
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