Fig 1: Three biological functions of NRF3 in cancer. (A) NRF3 exhibits three biological functions by regulating gene expression in colon cancer. (Top) In colorectal cancer cells, NRF3, the expression of which is induced by the ß-catenin/T-cell transcription factor 4 (TCF4) complex, enhances the assembly of the 20S proteasome by inducing the proteasome maturation protein (POMP) chaperone gene. Consequently, the 20S proteasome degrades the tumor suppressors p53 and retinoblastoma (Rb) in a ubiquitin-independent manner, preventing cell cycle arrest and apoptosis. (Middle) NRF3 is also induced by the NF-kB complex, including RELA in colon cancer cells, and activates cell proliferation by repressing the CDK inhibitor DUX4 gene and consequently activating CDK1 [22]. (Bottom) NRF3 represses the translation of NRF1 by inducing cytoplasmic polyadenylation element-binding protein 3 (CPEB3) and modulates basal proteasome activity in colon cancer cells [27]. (B) Schematic representation of the molecular mechanisms of proteasome assembly. The 26S proteasome comprises 20S and 19S proteasomes containing 66 subunits [28,29,30]. The assembly of each proteasome complex is tightly regulated in a coordinated manner by distinct chaperones. The 20S proteasome is assembled by proteasome assembling chaperone 1–4 (PAC1–PAC4) and POMP chaperones.
Fig 2: Conceptual hypotheses of the functional significance of NRF3 in cancer. The identification of the NRF3–POMP–20S proteasome axis allowed us to propose two conceptual hypotheses. (A) During the development of colorectal cancer, mutation of APC or ß-catenin in the Wnt pathway is a crucial initial event that activates the oncogene ß-catenin, and mutation of TP53 is the final event in carcinogenesis. In normal cells, activation of individual oncogenes, namely, “oncogenic stress“, activates p53 and Rb by stimulating the tumor suppressors ARF and p16, leading to cell cycle arrest and apoptosis. This response of normal cells confers cytoprotection against oncogenic stress. The NRF3–POMP–20S proteasome axis may eliminate the oncogenic stress response in normal cells to enable tumorigenesis. (B) The NRF3–POMP–20S proteasome axis represses the biological functions of p53 and Rb via proteasomal degradation. The advantage of this mechanism may be that repression occurs without a two-hit mutation of these genes.
Fig 3: (a) Kaplan-Meier (n = 25). High cytoplasmic NRF3 expression (cut-off 110) is associated with worse melanoma-specific survival within a group of patients with nodal metastases at the time of diagnosis. (b) Primary melanoma cases with high and low NRF3 expression. (c) A TIMER2.0 Kaplan-Meier plot based on TCGA database sample sets [18]. NFE2L3 mRNA expression in primary and metastatic melanomas (n = 471). Low expressors have a worse survival.
Fig 4: Immunohistochemical expression of NRF3 in benign naevus (a), dysplastic naevus (b), primary melanoma (c), and metastatic melanoma from a lymph node (d). The expression level is decreasing from benign to dysplastic and malignant samples.
Fig 5: mRNA expression. (a) Pooled Gene Expression Omnibus data from three different cDNA microarray studies including the expression levels of NRF3 show varying levels between benign, dysplastic, and malignant conditions. The only observed statistical significance is indicated. (b) A TIMER2.0 expression plot based on TCGA database sample sets [18]. Skin cutaneous melanoma and melanoma metastasis groups are highlighted with a red box. NFE2L3 mRNA levels increase significantly between melanoma tumour and metastasis groups (***p value < 0.001).
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