Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers

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115

The Kelch-like ECH-associated protein 1 (KEAP1)—Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1–NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.

Section: Roles Of Nrf2 In Cancer Progressionmentioning

confidence: 99%

The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment

Taguchi

Yamamoto

2020

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115

“…Moreover, liver-specific knockout of Keap1 (e.g., Keap1 FA/FA ; Alb-Cre mice) has not been reported to result in hepatocellular carcinoma, despite the animals having been first reported in 2006 [182]. Furthermore, persistent hyperactivation of NRF2 in human A549 lung cancer cells results in enhancer remodelling, allowing transcriptional activation of NOTCH3 by an NRF2-CEBPB complex that strongly supports tumourigenesis, and which is not observed in normal cells under stress conditions, indicating that continual activation of NRF2 in cancer cells results in overexpression of an enlarged battery of genes that is distinct from that induced by NRF2 in normal cells [183].…”

Section: Constitutive Activation Of Nrf2 Supports Post-initiation Stages Of Cancermentioning

confidence: 99%

NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis

Robertson

Dinkova‐Kostova

Hayes

2020

NF-E2 p45-related factor 2 (NRF2, encoded in the human by NFE2L2) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated. In such cases, its overexpressed target genes support the promotion and progression of cancer by suppressing oxidative stress, because they constitutively increase the capacity to scavenge reactive oxygen species (ROS), and they support cell proliferation by increasing ribonucleotide synthesis, serine biosynthesis and autophagy. Herein, we describe cancer chemoprevention and the discovery of the essential role played by NRF2 in orchestrating protection against chemical carcinogenesis. We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer. Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive. Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2. Lastly, as NRF2 upregulation is associated with resistance to cancer chemotherapy and radiotherapy, we describe strategies that might be employed to suppress growth and overcome drug resistance in tumours with overactive NRF2.

“…Cancer cells with the persistent activation of NRF2 rely heavily on NRF2 for proliferation, tumorigenesis, therapeutic resistance, and the maintenance of cancer stemness [ 18 , 21 ]. This NRF2 addiction status of cancer cells [ 52 ] is supported by potent antioxidant and detoxifying functions and unique metabolic adaptation [ 19 , 53 ] ( Figure 2 ).…”

Section: Contributions Of Nrf2 and Nrf1 To Cancer Malignancymentioning

confidence: 99%

“…Reactive electrophile species attack specific cysteine residues and provoke structural changes in the KEAP1 protein, causing a functional decline of KEAP1–CUL3 E3 ubiquitin ligase and consequent stabilization of NRF2 [ 13 , 14 , 15 , 16 , 17 ]. In addition to the above-mentioned cytoprotective functions of the KEAP1–NRF2 axis, we and other groups have reported NRF2-dependent metabolic and epigenetic shifts in cancer cells [ 18 , 19 , 20 , 21 ]. Somatic mutations of the KEAP1 gene, causing the constitutive activation of NRF2, were found among lung cancer patients and confer a robust growth advantage and tumor-initiating ability on cancers through the promotion of metabolic reprogramming and enhancement of cancer stemness [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 97%

Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer

Sekine

Motohashi

2021

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Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap‘n’collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.