Abstract
NRF3 (NFE2L3) belongs to the CNC-basic leucine zipper transcription factor family. An NRF3 homolog, NRF1 (NFE2L1), induces the expression of proteasome-related genes in response to proteasome inhibition. Another homolog, NRF2 (NFE2L2), induces the expression of genes related to antioxidant responses and encodes metabolic enzymes in response to oxidative stress. Dysfunction of each homolog causes several diseases, such as neurodegenerative diseases and cancer development. However, NRF3 target genes and their biological roles remain unknown. This review summarizes our recent reports that showed NRF3-regulated transcriptional axes for protein and lipid homeostasis. NRF3 induces the gene expression of POMP for 20S proteasome assembly and CPEB3 for NRF1 translational repression, inhibiting tumor suppression responses, including cell-cycle arrest and apoptosis, with resistance to a proteasome inhibitor anticancer agent bortezomib. NRF3 also promotes mevalonate biosynthesis by inducing SREBP2 and HMGCR gene expression, and reduces the intracellular levels of neural fatty acids by inducing GGPS1 gene expression. In parallel, NRF3 induces macropinocytosis for cholesterol uptake by inducing RAB5 gene expression. Finally, this review mentions not only the pathophysiological aspects of these NRF3-regulated axes for cancer cell growth and anti-obesity potential but also their possible role in obesity-induced cancer development.
Highlights
Protein and lipid homeostasis is crucial for cell survival and proliferation, and the defects interfere with several diseases, such as neurodegeneration, cancer development, metabolic disorder, and obesity [1,2,3,4]
We have identified several NRF3 target genes that coordinate protein and lipid homeostasis by gene expression analysis based on DNA microarray, real-time quantitative PCR, and chromatin immunoprecipitation (ChIP) experiments
NRF3 induces the expression of proteasome-related genes in parallel with NRF1 translational repression by inducing cytoplasmic polyadenylation element-binding protein 3 (CPEB3) expression [32]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Kelch-like ECH-associated protein 1 (Keap1)-null mice demonstrate postnatal lethality by the constitutive activation of Nrf2 [17]. NRF3 and NRF1 proteins are anchored to the endoplasmic reticulum (ER), and are degraded through ER-associated degradation Proteotoxic stress, such as proteasome inhibition, leads to the cleavage of these proteins by the aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), resulting in the nuclear translocation of cleaved. This review first introduces that NRF3 promotes cancer development through proteasome regulation, by inducing the gene regulation of proteasome maturation protein (POMP) [31] and cytoplasmic polyadenylation element-binding protein 3 (CPEB3) [32]. This review describes the gene expression network of NRF3-regulated lipid metabolism, including sterol regulatory element-binding protein 2 (SREBP2) and hydroxy-methylglutaryl-CoA reductase (HMGCR) [33]. This review remarks on the pathophysiological potential of these NRF3-regulated axes for cancer and obesity
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