Long-isoform NFE2L1 silencing inhibits acquisition of malignant phenotypes induced by arsenite in human bronchial epithelial cells

Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer

“…However, long-isoform NFE2L1 promotes cancer invasion and metastasis under chronic stress conditions. In human bronchial epithelial BEAS-2B cells, long-term arsenite exposure induced long-isoform NFE2L1 upregulation, which promotes EMT by positively regulating Snail1 transcription [149]. Gene set enrichment analysis and prognosis analysis indicated that NFE2L1 could be a key transcription factor in the acquisition of metastasis potential in ovarian cancer cells [150].…”

Unravelling the role of NFE2L1 in stress responses and related diseases

“…Accumulating evidence has unravelled that NFE2L1 exerts influence over adipocyte hypertrophy, inflammation, and insulin resistance through the regulation of redox balance [ 75 ], proteostasis [ 50 ], and mitochondrial homeostasis [ 116 ]. Thus, NFE2L1 dysfunction can instigate the spontaneous onset and advancement of various conditions including cancers [ [12] , [13] , [14] , [15] ], neurodegenerative diseases [ 20 ], inflammatory and autoimmune diseases [ [16] , [17] , [18] , [19] ], and vascular diseases [ 22 ] ( Table 2 ). The upstream regulators and downstream targets of NFE2L1 are also summarized in Table 2 .…”

“…Mechanistically, the stress-responsive NFE2L1 exerts control over crucial aspects of cancer biology, encompassing proliferation, epithelial-mesenchymal transition (EMT), invasion, metastasis, cell cycle progression, cell stemness, and immune infiltration. Consequently, NFE2L1 either hinders or promotes the development and progression of malignancies [ [12] , [13] , [14] , [15] ]. Despite progresses in curative surgery and perioperative chemotherapy, patients afflicted with advanced metastases continue to face unfavourable prognoses.…”

“…Persistent toxic stress can induce several cancers, for instance, prolonged arsenic exposure is highly linked to lung cancer development. The overexpression of long-isoform of NFE2L1-L can accelerate EMT process by enhancing EMT inducer SNAIL1 and decreasing epithelial biomarker E-cadherin in arsenite-induced lung cancer [ 13 ]. Therefore, NFE2L1 may enhance cancer cells’ chemoresistance to metal-based therapy to hamper the efficacy of chemotherapy.…”

“…Global knockout of NFE2L1 in mice leads to embryonic lethality [ 10 , 11 ]. Furthermore, tissue-specific knockout of NFE2L1 was clarified to result in 1) proteostasis-related diseases encompassing distinct cancers [ [12] , [13] , [14] , [15] ], inflammatory diseases [ [16] , [17] , [18] , [19] ], neurodegenerative diseases including Alzheimer’s disease [ 20 ], and Parkinson’s disease [ 21 ], 2) cellular redox-related disorders such as cardiovascular diseases (CVDs) [ 22 ]. Notably, NFE2L2 deficiency does not affect proteasome activity triggered under basal or proteotoxic stress [ 19 ], while NFE2L1 has been reported to provide greater cell protection and stress adaptation compared to NFE2L2 [ 22 ].…”