Special Issue "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).

Special Issue Editors

Prof. Dr. Amedeo Columbano
Website SciProfiles
Guest Editor
Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
Interests: Hepatocellular carcinoma; Thyroid hormones; NAFLD/NASH; Metabolic Reprogramming; microRNA; Nrf2-Keap1 pathway; Nuclear receptors
Prof. Dr. Silvia Giordano
Website
Guest Editor
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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (4 papers)

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Research

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Open AccessArticle
Prognostic Significance of Oxidation Pathway Mutations in Recurrent Laryngeal Squamous Cell Carcinoma
Cancers 2020, 12(11), 3081; https://doi.org/10.3390/cancers12113081 - 22 Oct 2020
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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Open AccessReview
Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer
Cancers 2020, 12(10), 3023; https://doi.org/10.3390/cancers12103023 - 17 Oct 2020
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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Open AccessReview
Nrf2 in Neoplastic and Non-Neoplastic Liver Diseases
Cancers 2020, 12(10), 2932; https://doi.org/10.3390/cancers12102932 - 12 Oct 2020
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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Open AccessReview
Roles of NRF3 in the Hallmarks of Cancer: Proteasomal Inactivation of Tumor Suppressors
Cancers 2020, 12(9), 2681; https://doi.org/10.3390/cancers12092681 - 20 Sep 2020
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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