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The physiological roles of the NRF2-related transcription factor NRF3 (NFE2L3) have remained unknown for decades. The remarkable development of human cancer genome databases has led to strong suggestions that NRF3 has functional significance in cancer; specifically, high NRF3 mRNA levels are induced in many cancer types, such as colorectal cancer and pancreatic adenocarcinoma, and are associated with poor prognosis. On the basis of this information, the involvement of NRF3 in tumorigenesis and cancer malignancy has been recently proposed. NRF3 confers cancer cells with selective growth advantages by enhancing 20S proteasome assembly through induction of the chaperone gene proteasome maturation protein (POMP) and consequently promoting degradation of the tumor suppressors p53 and retinoblastoma (Rb) in a ubiquitin-independent manner. This new finding offers insight into the proteasomal but not the genetic inactivation mechanism of tumor suppressors. Moreover, NRF3 promotes cancer malignancy-related processes, including metastasis and angiogenesis. Finally, the molecular mechanisms underlying NRF3 activation have been elucidated, and this knowledge is expected to provide many insights that are useful for the development of anticancer drugs that attenuate NRF3 transcriptional activity. Collectively, the evidence indicates that NRF3 confers cells with six so-called “hallmarks of cancer”, implying that it exhibits cancer driver gene-like function. This review describes recent research advances regarding the newly discovered addiction of cancer cells to NRF3 compared to NRF2.

Accumulating evidence has revealed that human cancers develop by sequentially mutating pivotal genes, including driver genes, and acquiring cancer hallmarks. For instance, cancer cells are addicted to the transcription factor NRF2 (NFE2L2), which is a driver gene that utilizes the cellular cytoprotection system against oxidative stress and metabolic pathway reprogramming for sustaining high growth. Our group has recently discovered a new addiction to the NRF2‐related factor NRF3 (NFE2L3) in cancer. For many years, the physiological function of NRF3 remained obscure, in part because Nrf3‐deficient mice do not show apparent abnormalities. Nevertheless, human cancer genome databases suggest critical roles of NRF3 in cancer because of high NRF3 mRNA induction in several cancer types, such as colorectal cancer and pancreatic adenocarcinoma, with a poor prognosis. We found that NRF3 promotes tumor growth and malignancy by activating ubiquitin‐independent 20S proteasome assembly through inducing the expression of the proteasome maturation protein (POMP) chaperone and thereby degrading the tumor suppressors p53 and Rb. The NRF3‐POMP‐20S proteasome axis has an entirely different effect on cancer than NRF2. In this review, we describe recent research advances regarding the new cancer effector NRF3, including unclarified ubiquitin‐independent proteolysis by the NRF3‐POMP‐20S proteasome axis. The expected development of cancer therapeutic interventions for this axis is also discussed. Cancer cells hijack cellular systems for sustaining high growth by acquiring gene mutations. For example, they are addicted to the transcription factor NRF2 (NFE2L2). We herein summarize recent research advances regarding the new cancer effector NRF3 (NFE2L3), including unclarified ubiquitin‐independent proteolysis by the NRF3‐POMP‐20S proteasome axis.

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 ubiquitin‒proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood. Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62 / SQSTM1 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of Ser403 in p62. Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.

Pernicious anemia is a macrocytic anemia caused by vitamin B12 deficiency that results from a lack of intrinsic factor. Lack of intrinsic factor may be caused by atrophic gastritis and damage to the oxyntic mucosa and parietal cells, which normally produce hydrochloric acid and intrinsic factor. Glossitis presents in up to 25% of people with pernicious anemia, initially as bright red plaques that may evolve into atrophy of the lingual papillae. Oral manifestations of pernicious anemia, including glossitis and stomatitis, may occur in the absence of anemia and represent an early clinical sign of vitamin B12 deficiency. Other causes of glossitis include nutritional deficiencies of vitamin B12, folic acid, riboflavin and niacin. Here, Kobayashi and Iwasaki examine the case of a 69-year-old Japanese woman with pernicious anemia.

Impaired turnover of the autophagy substrate p62 leads to liver injury. p62 inhibits the ubiquitin ligase Keap1, leading to stabilization of the transcription factor Nrf2. High levels of p62 in autophagy deficient animals leads to unusually high expression of Nrf2 targets genes and results in liver injury. Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.

To evaluate the corneal characteristics after Descemet membrane endothelial keratoplasty (DMEK) compared with normal corneas. Patients who underwent DMEK at Yokohama Minami Kyosai Hospital were included and prospectively evaluated pre-operatively and at postoperative months 1, 3, 6, and 12, and compared to healthy controls. Corneal characteristics evaluated included corneal curvature (keratometric value [KV]; D), central corneal thickness (CCT), peripheral corneal thickness (PCT), and corneal higher-order aberrations [HOAs] at 6.0 mm diameter, calculated by anterior segment optical coherence tomography and logarithm of the minimal angle of resolution [logMAR]. A total of 30 eyes of 30 patients (6 men, 24 women, mean age 73.4 ± 7.4 years) were included and compared with 31 age-matched healthy control eyes (13 men, 18 women; mean age 73.0 ± 6.7 years). LogMAR after DMEK improved from 0.87 ± 0.07 preoperatively to 0.04 ± 0.07 at 12 months postoperatively (p<0.001). Although anterior KVs of DMEK eyes were similar to those of control eyes, posterior KVs were significantly larger (-6.4 ± 0.3 D vs. -6.3 ± 0.2 D; p = 0.02). Total HOAs after DMEK improved from 1.94 ± 1.05 μm preoperatively to 1.05 ± 0.16 μm at 12 months postoperatively (p<0.001), which was significantly higher than that in control eyes (0.63 ± 0.06) (p<0.001). Despite the similar CCTs in the two groups, the PCT was significantly larger in DMEK eyes (704 ± 41 μm vs 669 ± 38 μm, p = 0.002) at 12 months. Despite achieving good visual function and excellent corneal clarity, eyes that underwent DMEK showed a steeper posterior KV and higher corneal HOAs than normal eyes even at 12 months after surgery.

Accumulated evidence suggests a physiological relationship between the transcription factor NRF3 (NFE2L3) and cancers. Under physiological conditions, NRF3 is repressed by its endoplasmic reticulum (ER) sequestration. In response to unidentified signals, NRF3 enters the nucleus and modulates gene expression. However, molecular mechanisms underlying the nuclear translocation of NRF3 and its target gene in cancer cells remain poorly understood. We herein report that multiple regulation of NRF3 activities controls cell proliferation. Our analyses reveal that under physiological conditions, NRF3 is rapidly degraded by the ER-associated degradation (ERAD) ubiquitin ligase HRD1 and valosin-containing protein (VCP) in the cytoplasm. Furthermore, NRF3 is also degraded by β-TRCP, an adaptor for the Skp1-Cul1-F-box protein (SCF) ubiquitin ligase in the nucleus. The nuclear translocation of NRF3 from the ER requires the aspartic protease DNA-damage inducible 1 homolog 2 (DDI2) but does not require inhibition of its HRD1-VCP-mediated degradation. Finally, NRF3 mediates gene expression of the cell cycle regulator U2AF homology motif kinase 1 (UHMK1) for cell proliferation. Collectively, our study provides us many insights into the molecular regulation and biological function of NRF3 in cancer cells.

We aimed to investigate the clinical characteristics and risk factors for graft rejection after keratoplasty in Japanese patients. We enrolled 730 cases (566 patients) of penetrating keratoplasty (PK, N = 198), Descemet’s stripping automated endothelial keratoplasty (DSAEK, N = 277), non-Descemet’s stripping automated endothelial keratoplasty (nDSAEK, N = 138), and Descemet membrane endothelial keratoplasty (DMEK, N = 117). The incidence, clinical characteristics, and possible risk factors for graft rejection were analyzed. Graft rejection occurred in 65 cases (56 patients, 8.9%). The incidence rate of rejection was highest with PK (3.45/100 person-years), followed by DSAEK (2.34), nDSAEK (1.55), and DMEK (0.24). Cox regression analysis revealed keratoplasty type, younger age, indications (such as failed keratoplasty and infection), and steroid eyedrop use as possible risk factors. In the multivariate model adjusting baseline characteristics, PK and DSAEK had significantly higher hazard ratios (HRs) than DMEK (HR = 13.6, 95% confidence interval [CI] [1.83, 101] for PK, 7.77 [1.03, 58.6] for DSAEK). Although not statistically significant, the HR estimate of nDSAEK to DMEK (HR = 7.64, 95% CI [0.98, 59.6]) indicated higher HR in nDSAEK than in DMEK. DMEK is the favorable option among the four surgical procedures to avoid graft rejection after keratoplasty.

To investigate the factors associated with endothelial survival after Descemet's membrane endothelial keratoplasty (DMEK) in eyes of Asian patients with bullous keratopathy (BK). In this retrospective, consecutive interventional case series, 72 eyes of 72 patients who underwent DMEK were evaluated. Best corrected visual acuity (BCVA) and corneal endothelial cell density (ECD) were assessed at 12 months postoperatively. Multiple regression analysis was performed to assess parameters such as age, sex, axial length, preoperative visual acuity, re-bubbling, the ratio of graft to cornea area, iris damage scores, types of filling gases, air or SF.sub.6 volume in the anterior chamber (AC) on postoperative day 1, and ECD loss rates at 12 months postoperatively. BCVA improved significantly at 12 months after DMEK (P < .001). The rate of ECD loss at 12 months after DMEK was 54.4 ± 16.1%. Multiple linear regression analysis showed that a larger ratio of graft to corneal area (P = 0.0061) and higher donor ECD (P = 0.042) were the primary factors for a lower ECD loss rate at 12 months after DMEK. A relatively larger graft size compared to the host cornea and more donor ECD might help endothelial survival in patients with BK. Moreover, for such patients, the surgeon should attempt to use a relatively larger graft size when performing DMEK, particularly in Asian eyes.