miR-106b-5p targets tumor suppressor gene SETD2 to inactive its function in clear cell renal cell carcinoma

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.

Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients

“…In comparison, IHC could detect the protein expression of a whole block section, which is more objective. Second, the SETD2 gene inactive mutation may not be the only reason leading to its protein deficiency, alternative ways exist, such as miR-106b-5p, which could target SETD2 and inactivate its function in ccRCC (22). Considering the important role of SETD2 protein in kidney cancer formation, we recommend further study focusing on the mechanism of SETD2 protein deficiency.…”

MiR-106b-5p Promotes Proliferation and Inhibits Apoptosis by Regulating BTG3 in Non-Small Cell Lung Cancer

“…It’s over-expression in colorectal cancer promoted cell migration and invasion by directly targeting DLC1 [42]. And MicroRNA-106b-5p was also certified as a suppressor in expression of SETD2 and plays an important role in regulating ccRCC cell proliferation and apoptosis through SETD2-dependent way [43]. Nevertheless, to our knowledge, the function of miR-106b-5p in NSCLC cells still remains unclear.…”

Shaping the cellular landscape with Set2/SETD2 methylation

“…The long noncoding RNA HOTAIR can bind to the promoter region of SETD2 and inhibit the recruitment of pro-transcription factors such as CREB, P300, and RNAPII [72]. At the post-transcriptional level, another non-coding RNA, miR-106b-5p, binds SETD2 mRNA and inhibits its translation in clear cell renal cell carcinoma (ccRCC) [73]. As discussed below, SETD2 is frequently mutated and/or inactivated in ccRCCs and other cancer types.…”