Therapeutic potential of NR4A1 in cancer: Focus on metabolism

Abstract

Metabolic reprogramming is a vital hallmark of cancer, and it provides the necessary energy and biological materials to support the continuous proliferation and survival of tumor cells. NR4A1 is belonging to nuclear subfamily 4 (NR4A) receptors. NR4A1 plays diverse roles in many tumors, including melanoma, colorectal cancer, breast cancer, and hepatocellular cancer, to regulate cell growth, apoptosis, metastasis. Recent reports shown that NR4A1 exhibits unique metabolic regulating effects in cancers. This receptor was first found to mediate glycolysis via key enzymes glucose transporters (GLUTs), hexokinase 2 (HK2), fructose phosphate kinase (PFK), and pyruvate kinase (PK). Then its functions extended to fatty acid synthesis by modulating CD36, fatty acid-binding proteins (FABPs), sterol regulatory element-binding protein 1 (SREBP1), glutamine by Myc, mammalian target of rapamycin (mTOR), and hypoxia-inducible factors alpha (HIF-1α), respectively. In addition, NR4A1 is involving in amino acid metabolism and tumor immunity by metabolic processes. More and more NR4A1 ligands are found to participate in tumor metabolic reprogramming, suggesting that regulating NR4A1 by novel ligands is a promising approach to alter metabolism signaling pathways in cancer therapy. Basic on this, this review highlighted the diverse metabolic roles of NR4A1 in cancers, which provides vital references for the clinical application.

Trained immunity induced by high‐salt diet impedes stroke recovery

“…The transcriptomic analysis identified HSD downregulated NR4a1 and NR4a3 with or without ICH. These transcription factors belong to the NR4a family, which regulate the expansion of hematopoietic progenitors (Land et al , 2015; Freire & Conneely, 2018) and glucose metabolism (Corrocher et al , 2018; Deng et al , 2022) as well as inflammatory responses and mitochondrial metabolism in macrophages (Koenis et al , 2018). To assess whether the effects of HSD are mediated by the NR4a family, we generated an NR4a triple‐knockout line (termed NR4a TKO) by crossing NR4a3 −/− mice with mice expressing Cre recombinase under the myeloid‐specific LysM promoter and carrying loxP‐flanked alleles encoding NR4a1 and NR4a2 (Sekiya et al , 2013).…”

Oxygen–Glucose Deprivation Increases NR4A1 Expression and Promotes Its Extranuclear Translocation in Mouse Astrocytes

“…Moreover, Nr4a triple deficiency (absence of NR4A1, NR4A2, and NR4A3) aberrantly converts Treg precursors into pathogenic self-reactive cells, suggesting that the NR4A family of receptors plays crucial roles in both Treg cell development and the elimination of cells that fail to mature into Tregs [ 22 ]. Increasing evidence suggests that NR4A1 has several metabolic functions in cancers and is involved in regulating glycolysis, fatty acid synthesis, and the metabolism of glutamine and amino acids [ 23 ]. NR4A1 and NR4A3 also function as tumor suppressors of myeloid leukemia, and downregulation of NR4A1 and NR4A3 expression is a common feature of the leukemic blast [ 24 ].…”

Effects of Long Non-Coding RNAs Induced by the Gut Microbiome on Regulating the Development of Colorectal Cancer

“…It can help maintain intestinal homeostasis by preventing the expression of pro-inflammatory cytokines and regulating the function of intestinal macrophages by inhibiting histone deacetylases [ 72 , 73 , 74 ]. The lncRNA LncLy6C, induced by the microbiota metabolite butyrate, binds to the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) and several lysine methyltransferases of H3K4me3, specifically encouraging the enrichment of C/EBPβ and H3K4me3 marks on the promoter region of Nr4A1, nuclear subfamily 4 (NR4A) receptor, which is overexpressed in CRC and plays a central role in controlling cell proliferation, apoptosis, and metastasis [ 37 , 75 ]. This causes the upregulated expression of Nr4A1, promoting the differentiation of Ly6C high inflammatory monocytes into Ly6C int/neg resident macrophages [ 37 ] ( Figure 4 ).…”