Pathophysiological Potentials of NRF3-Regulated Transcriptional Axes in Protein and Lipid Homeostasis

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.

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

“…The mRNA expression of the third family member, NRF3, is abundant in the cornea, skin, and bladder, but is low in the major detoxification sites, notably the liver [27]. The NRF3 function remains undetermined [28][29][30][31], though recent propositions have implicated it in tumorigenesis and cancer malignancy [27,32].…”

The rich evolutionary history of the ROS metabolic arsenal shapes its mechanistic plasticity at the onset of metazoan regeneration

“…In addition, it is well documented that within the Nrf superfamily, Nrf2 is involved in the antioxidative response (Zhang et al 2009;Zhao et al 2011). This is not the case for Nrf1 and Nrf3, two transcription factors that are involved in protein and lipid homeostasis (Radhakrishnan et al 2010;Lee et al 2013;Waku and Kobayashi 2021). As Nrf1, 2 and 3 result from a relatively recent duplication in gnathosomes, the ancestral function of Nrf in metazoans remains unknown.…”

Transcriptional Regulation and Its Misregulation in Human Diseases

“…In this Special Issue, a total of 18 excellent and interesting papers [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], consisting of 13 original research studies [3][4][5][6][10][11][12][14][15][16][18][19][20], as well as five reviews, are published [7][8][9]13,17]. They cover many subjects of transcriptional regulation, including studies on cis-regulatory elements, transcription factors (TF), chromatin regulators, and ncRNAs.…”

“…Noteworthy, SNAI1 is involved in the formation of cancer metastases by epigenetic regulation and post-translational modifications [7]. The Waku and Kobayashi [8] review describes the pathophysiological aspects of the biomolecular pathways regulated by NRF3 (NFE2L3; NFE2-like BZIP Transcription Factor 3), a transcription factor belonging to the cap'n'collar (CNC)-based leucine zipper family and functioning through proteasome regulation. The NRF3 factor and its regulated axes are involved in cancer cell growth and have anti-obesity potential, thus suggesting a possible role in the development of obesityinduced cancer [8].…”

“…The Waku and Kobayashi [8] review describes the pathophysiological aspects of the biomolecular pathways regulated by NRF3 (NFE2L3; NFE2-like BZIP Transcription Factor 3), a transcription factor belonging to the cap'n'collar (CNC)-based leucine zipper family and functioning through proteasome regulation. The NRF3 factor and its regulated axes are involved in cancer cell growth and have anti-obesity potential, thus suggesting a possible role in the development of obesityinduced cancer [8]. Finally, Rai V. et al critically summarized the studies performed on the regeneration of sensory hair cells (HCs) in adult mammalian cochleas to elucidate the molecular pathways, and particularly transcription factors, involved in the regeneration of cochlear HCs, which aids in proposing a biological approach for better therapeutics to treat hearing loss and to restore hearing [9].…”