Selective repression of the oncogene cyclin D1 by the tumor suppressor miR-206 in cancers

Abstract

MicroRNAs (miRNAs) are deregulated in cancer and have been shown to exhibit both oncogenic and tumor suppressive functions. Although the functional effects of several miRNAs have been elucidated, those of many remain to be discovered. In silico analysis identified microRNA-206 (miR-206) binding sites in the 3′-untranslated regions (3′-UTR) of both the mouse and human CCND1 gene. Cyclin D1 is a recognized oncogene involved in direct phosphorylation of the retinoblastoma (Rb) protein and promoting cell cycle transition from G1 to S. miR-206 specifically binds to the CCND1 3′-UTR and mediates reduction of both cyclin D1 protein and mRNA. Expression of miR-206 induced a G1 arrest and a decrease in cell proliferation in breast cancer cells. Ectopic expression of miRNA-resistant cyclin D1 was able to reverse the miR-206-induced decrease in cell proliferation. Therefore, we identified miR-206 as an activator of cell cycle arrest resulting in a decrease in cell proliferation that is dependent on the inhibition of cyclin D1. Interestingly, prostatic cancer (PCa) cells express low levels of miR-206 resulting in deregulated cyclin D1 expression compared with non-transformed primary prostatic epithelial cells (PrEC). Finally, we demonstrate that cyclin D1 is regulated by miR-206 in PrEC but not in PCa cells and this is due to the absence of a CCND1 3'-UTR in these cells. This suggests that miR-206-based anti-cyclin D1 targeted therapy would be beneficial in cancers where cyclin D1 is overexpressed and contains a 3′-UTR.

HDAC9 overexpression confers invasive and angiogenic potential to triple negative breast cancer cells via modulating microRNA-206

“…Several investigations have demonstrated that decreased miR-206 expression is involved in breast cancer proliferation [43, 44]. Our previous studies show that miR-206 is antagonistically involved in TNBC invasion and angiogenesis through modulating VEGF and MAPK3 [35].…”

How interacting pathways are regulated by miRNAs in breast cancer subtypes

“…It has been found to be down-regulated in ERα-positive BC, both in patient samples and BC cell lines [61], and in lymph node metastatic BC [62]. A critical role of Hsa-miR-206 has been recently demonstrated in the regulation of the 3′ UTR of cyclin D1, inducing G1 arrest and a decrease in cell proliferation in BC cells [63], thus suggesting a potential role as a tumour suppressor. It has been also shown that Hsa-miR-206 regulates ERα via interaction with its 3′ UTR [64], demonstrating a specific function in most aggressive types of BC.…”

Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting

“…As was expected, miR-206 modulates gene expression by the direct binding oftarget mRNA3 0 -UTR. miR-206 could specifically bind to the CCND1 3 0 -UTR and reducecyclin D1 expression, resulting inG1 arrest induction andproliferation inhibition in breast cancer cells [16].Emerging evidence has shown that miR-206 is involved in glucose metabolic reprogramming. miR-206 expression was demonstrated to be inversely correlated with pentose phosphate pathway (PPP) gene expression [17].…”