Regulation of Minichromosome Maintenance Gene Family by MicroRNA-1296 and Genistein in Prostate Cancer

Abstract

The minichromosome maintenance (MCM) gene family is essential for DNA replication and is frequently upregulated in various cancers. Here, we examined the role of MCM2 in prostate cancer and the effect of microRNA-1296 (miR-1296), genistein, and trichostatin A (TSA) on the MCM complex. Profiling results showed that expression of MCM genes was higher in tumor samples. Genistein and TSA significantly downregulated the expression of all MCM genes. Genistein, TSA, and small interfering RNA duplexes caused a significant decrease in the S phase of the cell cycle. There was also downregulation of CDT1, CDC7, and CDK2 genes, which govern loading of the MCM complex on chromatin. We also found that miR-1296 was significantly downregulated in prostate cancer samples. In PC3 cells, inhibition of miR-1296 upregulated both MCM2 mRNA and protein, whereas overexpression caused a significant decrease in MCM2 mRNA, protein, and the S phase of the cell cycle. MCM genes are excellent anticancer drug targets because they are essential DNA replication factors that are highly expressed in cancer cells. This is the first report showing anti-MCM effect by miR-1296, genistein, and TSA. TSA is undergoing clinical trials as a prostate cancer treatment but has high toxicity. Genistein, a natural, nontoxic dietary isoflavone, may be an advantageous therapeutic agent for treating prostate cancer. The use of RNA interference is currently being implemented as a gene-specific approach for molecular medicine. The specific downregulation of oncogenes by miR may contribute to novel therapeutic approaches in the treatment of prostate cancer.

Long Non-coding RNA HOTAIR Is Targeted and Regulated by miR-141 in Human Cancer Cells

“…We found that HOTAIR and miR-141 expression are inversely correlated in renal carcinoma cells. Genistein has potent biological activity, regulates several signaling pathways in cancer cells, and promotes cancer cell death (29,30,50,51), and we have found that genistein regulates miRNAs (33,(52)(53)(54). We also found that genistein decreases HOTAIR expression while stimulating miR-141 expression, showing an inverse effect.…”

Regulation of MicroRNAs by Natural Agents: New Strategies in Cancer Therapies

“…Inhibition of miR-1296 resulted in upregulation of MCM2 mRNA and protein and vice versa, strongly suggesting MCM2 as its target. Furthermore, MCM2 expression correlated with prostate cancer progression, whereby reduced expression of miR-1296 was observed in prostate carcinoma compared to benign prostate hyperplasia [56]. …”

Prostate cancer: The main risk and protective factors – Epigenetic modifications

“…A handful of studies have been led by other teams attempting to understand the mechanisms involved in the soy phytoestrogen-induced reversal of epigenetic alterations, and they all point to DNA methylation by gene promoters or histone modifications. Recent studies have shown that genistein and daidzein may be involved in another epigenetic modification -microRNA (miRNA) regulation [91,92].…”