Regulation of Nuclear Receptor Nur77 by miR-124

Abstract

The nuclear receptor Nur77 is commonly upregulated in adult cancers and has oncogenic functions. Nur77 is an immediate-early response gene that acts as a transcription factor to promote proliferation and protect cells from apoptosis. Conversely, Nur77 can translocate to the mitochondria and induce apoptosis upon treatment with various cytotoxic agents. Because Nur77 is upregulated in cancer and may have a role in cancer progression, it is of interest to understand the mechanism controlling its expression. MicroRNAs (miRNAs) are responsible for inhibiting translation of their target genes by binding to the 3ʹUTR and either degrading the mRNA or preventing it from being translated into protein, thereby making these non-coding endogenous RNAs vital regulators of every cellular process. Several miRNAs have been predicted to target Nur77; however, strong evidence showing the regulation of Nur77 by any miRNA is lacking. In this study, we used a luciferase reporter assay containing the 3ʹUTR of Nur77 to screen 296 miRNAs and found that miR-124, which is the most abundant miRNA in the brain and has a role in promoting neuronal differentiation, caused the greatest reduction in luciferase activity. Interestingly, we discovered an inverse relationship in Daoy medulloblastoma cells and undifferentiated granule neuron precursors in which Nur77 is upregulated and miR-124 is downregulated. Exogenous expression to further elevate Nur77 levels in Daoy cells increased proliferation and viability, but knocking down Nur77 via siRNA resulted in the opposite phenotype. Importantly, exogenous expression of miR-124 reduced Nur77 expression, cell viability, proliferation, and tumor spheroid size in 3D culture. In all, we have discovered miR-124 to be downregulated in instances of medulloblastoma in which Nur77 is upregulated, resulting in a proliferative state that abets cancer progression. This study provides evidence for increasing miR-124 expression as a potential therapy for cancers with elevated levels of Nur77.

RARβ acts as both an upstream regulator and downstream effector of miR‐22 , which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells

“…NUR77 transcriptional activity is expected to be reduced after cytoplasmic localization in response to combined HDAC inhibitors and RA treatment. When in the nucleus, NUR77 increases transcription of target genes, including antiapoptotic brain and reproductive organexpressed protein (BRE) and proproliferative cyclin D2 (CCND2) (26,28,36). DNA binding data generated by ChIP-qPCR revealed reduced NUR77 occupancy in the regulatory regions of the BRE and CCND2 genes after HDAC inhibitor and combination treatments.…”

“…One mechanism by which HDAC inhibitors can enhance retinoid-induced apoptosis is through induction and nuclear export of RA receptor b (RARb) and orphan nuclear receptor, nerve growth factor (NUR77) (24). NUR77 is overexpressed in multiple cancer types, including colon, liver, and pancreatic cancers, making NUR77 an attractive target for cancer treatment (26)(27)(28). When residing in the nucleus, NUR77 regulates the expression of proliferative cell cycle genes as well as survival genes (26,29,30).…”

“…In addition, NUR77 plays a role in TGF-b-induced migration and invasion of breast cancer cells (33). Recently, NUR77 was identified as a direct target of miR-124 in pediatric cancer cell lines, indicating the role of miRNA in the regulation of NUR77 (28). miR-22 has been shown to have HDAC inhibitory properties by reducing HDAC4 and sirtuin 1 (SIRT1) in rat cardiomyocytes and human hepatocellular carcinoma cells (3,11,12).…”

Brain Tumor Treatment: 2017 Update

“…Meanwhile, transfection of miR-124 or microR-137 promoted differentiation in CD133+ glioblastoma multiforme BTSCs and reduced glioblastoma multiforme cell proliferation in vitro (Silber, Lim et al 2008). miR-124 induced down regulation of Nur77 has been shown to reduce glioma cell viability, proliferation and invasiveness (Tenga, Beard et al 2016). miR-326 transfection has been shown to be cytotoxic to both normal glioma cells and glioma BTSCs, thus, inhibiting glioma tumorigenicity in mice bearing xenografts (Kefas, Comeau et al 2009).…”

The Roles of Nuclear Receptor NR4A1 in Cancer Cell Proliferation and Skeletal Muscle Differentiation

“…This study also found that miR-124 can suppress the transcriptional activity of NR4A1 in Daoy medulloblastoma cells. When miR-124 was exogenously expressed in these cells, proliferation and viability were significantly decreased [242]. Although miR-124 is predicted to target many other genes, it is possible that it is causing these anti-tumor effects through the suppression of NR4A1.…”