The KEAP1-NRF2 Pathway in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 45814

Special Issue Editors

Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, 09124 Cagliari, Italy
Interests: hepatocellular carcinoma; thyroid hormones; NAFLD/NASH; metabolic reprogramming; microRNA; Nrf2-Keap1 pathway; nuclear receptors
Department of Oncology, University of Torino, Candiolo, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
Interests: Gastroesophageal cancer; PDX; targeted therapy; resistance; liver cancer; NRF2

Special Issue Information

Dear Colleagues,

The transcription factor NRF2 is considered as part of the main defense mechanism of the cell against oxidative stress and a major regulator of cell survival. As a result, NRF2 has traditionally been deemed to be a tumor suppressor. However, it is now clear that NRF2 promotes survival not only of normal cells but also of cancer cells, suggesting that activation of NRF2 sustains progression to malignancy. Following the evidence that NRF2 activation is frequent in several human and experimental tumors in multiple tissues, and that genetic ablation of the gene completely prevents cancer development in experimental models, NRF2 has also become a prime candidate for targeted therapy in different tumor types.

While much of the focus has, so far, been on activation of the NRF2–KEAP1 pathway caused by Nrf2 or KEAP1 gene mutations or disruption of NRF2–KEAP1 binding, alternative mechanisms of activation have been proposed which might also play an important role. In HCC, for instance, a recent study shows that NRF2 activity depends on fructosamine-3-kinase (FN3K)—a kinase that triggers protein de-glycation—while another work found that the activity of the KEAP1/NRF2 pathway response is dependent on the histone chaperone facilitates chromatin transcription (FACT) protein. As we develop a better understanding of the molecular complexity underlying the different intracellular responses, we can ultimately hope to devise specific interventions for each of these different signaling mechanisms. This is of great relevance as, unfortunately, specific drugs directly aimed at blocking Nrf2 signaling are not yet available. In terms of therapeutic intervention, it is also of outmost relevance to understand whether distinct mechanisms are involved at different stages of cancer development.

With this Special Issue, we aim to present different contributions that will highlight the role of NRF2 signaling in different types of cancer, covering both basic and more (pre)clinical aspects as well as the current status of NRF2 inhibitors, in the hope of promoting advances in our understanding of targeting this complex pathway in human tumors.

Prof. Dr. Amedeo Columbano
Prof. Dr. Silvia Giordano
Guest Editors

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Keywords

  • Nrf2/Keap1 mutation
  • NRF2 family
  • human cancers
  • animal models
  • p62 and autophagy
  • epigenetics
  • NRF2-targeted drugs

Published Papers (10 papers)

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Research

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15 pages, 2192 KiB  
Article
High Expression of NRF2 Is Associated with Increased Tumor-Infiltrating Lymphocytes and Cancer Immunity in ER-Positive/HER2-Negative Breast Cancer
by Masanori Oshi, Fernando A. Angarita, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe
Cancers 2020, 12(12), 3856; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123856 - 21 Dec 2020
Cited by 33 | Viewed by 3652
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast [...] Read more.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). NRF2 expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High NRF2 ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. NRF2 expression was elevated in immune, stromal, and cancer cells. High NRF2 tumors were associated with high infiltration of immune cells (CD8+, CD4+, and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. NRF2 expression significantly correlated with area under the curve (AUC) of several drug response in multiple ER-positive breast cancer cell lines, however, there was no significant association between NRF2 and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high NRF2 breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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19 pages, 3225 KiB  
Article
Prognostic Significance of Oxidation Pathway Mutations in Recurrent Laryngeal Squamous Cell Carcinoma
by Molly E. Heft Neal, Apurva D. Bhangale, Andrew C. Birkeland, Jonathan B. McHugh, Andrew G. Shuman, Andrew J. Rosko, Paul L. Swiecicki, Matthew E. Spector and J. Chad Brenner
Cancers 2020, 12(11), 3081; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113081 - 22 Oct 2020
Cited by 7 | Viewed by 2168
Abstract
Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. [...] Read more.
Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. Sixty-two patients were sequenced using a targeted panel, of which twenty-two also underwent transcriptome sequencing. Alterations were grouped based on biologic pathways and survival outcomes were assessed using Kaplan-Meier analysis and multivariate cox regression. Select pathways were evaluated against The Cancer Genome Atlas (TCGA) data. Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, p = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, p = 0.02). Multivariate analysis showed mutations in the Oxidation pathway remained an independent predictor of disease specific survival (HR 3.2, 95% CI 1.1–9.2, p = 0.03). Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity. Further, TCGA analyses demonstrated the prognostic value of oxidation pathway alterations in previously untreated disease. Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer. These prognostic genetic biomarkers may inform precision medicine protocols and identify putatively targetable pathways to improve survival in this cohort. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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Review

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14 pages, 1576 KiB  
Review
Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer
by Hiroki Sekine and Hozumi Motohashi
Cancers 2021, 13(3), 541; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030541 - 01 Feb 2021
Cited by 29 | Viewed by 4173
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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21 pages, 2710 KiB  
Review
The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment
by Keiko Taguchi and Masayuki Yamamoto
Cancers 2021, 13(1), 46; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010046 - 26 Dec 2020
Cited by 91 | Viewed by 8055
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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22 pages, 1637 KiB  
Review
NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward
by Federico Pio Fabrizio, Angelo Sparaneo and Lucia Anna Muscarella
Cancers 2020, 12(12), 3621; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123621 - 03 Dec 2020
Cited by 18 | Viewed by 2908
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is the key transcription factor triggered by oxidative stress that moves in cells of the antioxidant response element (ARE)-antioxidant gene network against reactive oxygen species (ROS) cellular damage. In tumors, the NRF2 pathway represents one of [...] Read more.
Nuclear factor erythroid 2-related factor 2 (NRF2) is the key transcription factor triggered by oxidative stress that moves in cells of the antioxidant response element (ARE)-antioxidant gene network against reactive oxygen species (ROS) cellular damage. In tumors, the NRF2 pathway represents one of the most intriguing pathways that promotes chemo- and radioresistance of neoplastic cells and its activity is regulated by genetic and epigenetic mechanisms; some of these being poorly investigated in cancer. The noncoding RNA (ncRNA) network is governed by microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) and modulates a variety of cellular mechanisms linked to cancer onset and progression, both at transcriptional and post-transcriptional levels. In recent years, the scientific findings about the effects of ncRNA landscape variations on NRF2 machines are rapidly increasing and need to be continuously updated. Here, we review the latest knowledge about the link between NRF2 and ncRNA networks in cancer, thus focusing on their potential translational significance as key tumor biomarkers. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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48 pages, 2429 KiB  
Review
NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis
by Holly Robertson, Albena T. Dinkova-Kostova and John D. Hayes
Cancers 2020, 12(12), 3609; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123609 - 02 Dec 2020
Cited by 42 | Viewed by 6351
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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25 pages, 1158 KiB  
Review
Role of the KEAP1-NRF2 Axis in Renal Cell Carcinoma
by Sara Clerici and Alessandra Boletta
Cancers 2020, 12(11), 3458; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113458 - 20 Nov 2020
Cited by 15 | Viewed by 3290
Abstract
NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, [...] Read more.
NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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20 pages, 2007 KiB  
Review
Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer
by Janine M. DeBlasi and Gina M. DeNicola
Cancers 2020, 12(10), 3023; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103023 - 17 Oct 2020
Cited by 39 | Viewed by 5124
Abstract
The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting [...] Read more.
The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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28 pages, 2883 KiB  
Review
Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases
by Claudia Orrù, Silvia Giordano and Amedeo Columbano
Cancers 2020, 12(10), 2932; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102932 - 12 Oct 2020
Cited by 13 | Viewed by 4304
Abstract
Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents [...] Read more.
Activation of the Keap1/Nrf2 pathway, the most important cell defense signal, triggered to neutralize the harmful effects of electrophilic and oxidative stress, plays a crucial role in cell survival. Therefore, its ability to attenuate acute and chronic liver damage, where oxidative stress represents the key player, is not surprising. On the other hand, while Nrf2 promotes proliferation in cancer cells, its role in non-neoplastic hepatocytes is a matter of debate. Another topic of uncertainty concerns the nature of the mechanisms of Nrf2 activation in hepatocarcinogenesis. Indeed, it remains unclear what is the main mechanism behind the sustained activation of the Keap1/Nrf2 pathway in hepatocarcinogenesis. This raises doubts about the best strategies to therapeutically target this pathway. In this review, we will analyze and discuss our present knowledge concerning the role of Nrf2 in hepatic physiology and pathology, including hepatocellular carcinoma. In particular, we will critically examine and discuss some findings originating from animal models that raise questions that still need to be adequately answered. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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19 pages, 3215 KiB  
Review
Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors
by Akira Kobayashi
Cancers 2020, 12(9), 2681; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092681 - 20 Sep 2020
Cited by 27 | Viewed by 4615
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The KEAP1-NRF2 Pathway in Cancer)
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