Abstract
Simple SummaryThis review summarizes recent advances in our understanding of the physiological roles of the NFE2-related factor 2 (NRF2)-related transcription factor NRF3 in cancer. NRF3 confers cells with six so-called “hallmarks of cancer” through upregulating gene expression of specific target genes, leading to tumorigenesis and cancer malignancy. These driver gene-like functions of NRF3 in cancer are distinct from those of NRF2.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.
Highlights
In the past decade, remarkable advances in human cancer databases, including genome, transcriptome, proteome, epigenome, metabolome, and clinical data, have led to many insights into the biology of cancer and have suggested new concepts, such as driver and passenger gene mutations [1,2,3,4].Driver gene mutations confer tumor cells with selective growth advantages, and more than 200 driver genes, such as PIK3CA, SMAD4, and TP53, have been identified
NRF3 gene is remarkably upregulated in many cancer tissues, such as colorectal adenocarcinoma (COAD), rectal adenocarcinoma (READ), and pancreatic ductal adenocarcinoma (PDAC; it is annotated as PAAD within The Cancer Genome Atlas (TCGA)) (Figure 1)
The biological function of the 20S proteasome itself remains unclear, we found that 20S proteasome activation by the NRF3–proteasome maturation protein (POMP) axis leads to degradation of the tumor suppressor proteins p53 and retinoblastoma (Rb)
Summary
Remarkable advances in human cancer databases, including genome, transcriptome, proteome, epigenome, metabolome, and clinical data, have led to many insights into the biology of cancer and have suggested new concepts, such as driver and passenger gene mutations [1,2,3,4]. Cancer arises through a multistep mutagenic process whereby cancer cells acquire a common set of properties, named “the hallmarks of cancer”, originally proposed by Hanahan and Weinberg [1]. Current databases indicate an association between NRF3 expression and poor prognosis, suggesting an essential roles of NRF3 in cancer malignancy [13]. For this reason, NRF3 has attracted attention, and the number of studies reporting intriguing functions of NRF3 in cancer is gradually increasing. Recent findings show that NRF3 confers cells with selective growth advantages, namely, the six hallmarks of cancer (Figure 2), implying that NRF3 exhibits cancer driver gene-like functions. NRF3 confers cells with these capabilities by inducing the expression of the indicated genes. 1; CPEB3, cytoplasmic element (CPE)-binding protein 3; VEGFA, vascular endothelial growth factor A
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