Genetic and epigenetic regulation of the NRF2-KEAP1 pathway in human lung cancer

Camiña, Nuria; Penning, T.M.

doi:10.1038/s41416-021-01642-0

Cited by 26 publications

(20 citation statements)

References 96 publications

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“…Keap1, a repressor of Nrf2, is composed of four domains: broad complex‐Tramtrack‐Bric‐a‐brac (BTB), intervening region (IVR), double‐glycine repeat (DGR; also known as Kelch domain), and C‐terminal region (CTR). 71 The BTB domain has been reported to be associated with dimer formation. 72 The IVR domain contains a nuclear export sequence (NES), which is important for the cytoplasmic localization and reactivity of Keap1 in response to oxidative stimuli.…”

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

“…This is mediated by two reactive cysteine residues in the IVR: cysteine 273 (C273) and cysteine 288 (C288). 71 , 73 The two DGR/Kelch domains recruit Neh2 by differentially binding to the ETGE and DLG motifs of the Nrf2 molecule. 74 , 75 When oxidants are present, the DLG motif is freed from Keap1, preventing Nrf2 ubiquitination and subsequent destruction.…”

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

“…The IVR domain contains a nuclear export sequence (NES), which is important for the cytoplasmic localization and reactivity of Keap1 in response to oxidative stimuli. This is mediated by two reactive cysteine residues in the IVR: cysteine 273 (C273) and cysteine 288 (C288) 71,73 . The two DGR/Kelch domains recruit Neh2 by differentially binding to the ETGE and DLG motifs of the Nrf2 molecule 74,75 .…”

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

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Redox signaling at the crossroads of human health and disease

Zuo

Zhang

Luo

et al. 2022

MedComm

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Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases.

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Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

Section: Redox Signaling Network In Cellular Homeostasismentioning

confidence: 99%

See 2 more Smart Citations

Redox signaling at the crossroads of human health and disease

Zuo

Zhang

Luo

et al. 2022

MedComm

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“…Keap1 is the best regulator of Nrf2 via promoting its proteasomal degradation. In addition to the regulation of Nrf2 protein stability, we provide an update on various phytochemicals that regulate NRF2 via DNA methylation, histone modifications, and noncoding RNAs [ 57 ]. Targeting the epigenetic mechanisms of Nrf2 represents an attractive therapeutic strategy.…”

Section: Epigenetic Regulation Of Nrf2 Signalingmentioning

confidence: 99%

Target Nuclear Factor Erythroid 2-Related Factor 2 in Pulmonary Hypertension: Molecular Insight into Application

Qin

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor involved in maintaining redox balance and activates the expression of downstream antioxidant enzymes. Nrf2 has received wide attention considering its crucial role in oxidative and electrophilic stress. Large amounts of studies have demonstrated the protective role of Nrf2 activation in various pulmonary hypertension (pH) models. Additionally, various kinds of natural phytochemicals acting as Nrf2 activators prevent the development of pH and provide a novel and promising therapeutic insight for the treatment of pH. In the current review, we give a brief introduction of Nrf2 and focus on the role and mechanism of Nrf2 in the pathophysiology of pH and then review the relevant research of Nrf2 agonists in pH in both experimental research and clinical trials.

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Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

et al. 2022

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Recent evidence has indicated that overexpression of the epigenetic reader bromodomain‐containing protein 4 (BRD4) contributes to a poor prognosis of lung cancers, and the suppression of its expression promotes cell apoptosis and leads to tumor shrinkage. Proteolysis targeting chimera (PROTAC) has recently emerged as a promising therapeutic strategy with the capability to precisely degrade targeted proteins. Herein, a novel style of versatile nano‐PROTAC (CREATE (CRV‐LLC membrane/DS‐PLGA/dBET6)) is developed, which is constructed by using a pH/GSH (glutathione)‐responsive polymer (disulfide bond‐linked poly(lactic‐co‐glycolic acid), DS‐PLGA) to load BRD4‐targeted PROTAC (dBET6), followed by the camouflage with engineered lung cancer cell membranes with dual targeting capability. Notably, CREATE remarkably confers simultaneous targeting ability to lung cancer cells and tumor‐associated macrophages (TAMs). The pH/GSH‐responsive design improves the release of dBET6 payload from nanoparticles to induce pronounced apoptosis of both cells, which synergistically inhibits tumor growth in both subcutaneous and orthotopic tumor‐bearing mouse model. Furthermore, the efficient tumor inhibition is due to the direct elimination of lung cancer cells and TAMs, which remodels the tumor microenvironment. Taken together, the results elucidate the construction of a versatile nano‐PROTAC enables to eliminate both lung cancer cells and TAMs, which opens a new avenue for efficient lung cancer therapy via PROTAC.

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Genetic and epigenetic regulation of the NRF2-KEAP1 pathway in human lung cancer

Cited by 26 publications

References 96 publications

Redox signaling at the crossroads of human health and disease

Redox signaling at the crossroads of human health and disease

Target Nuclear Factor Erythroid 2-Related Factor 2 in Pulmonary Hypertension: Molecular Insight into Application

Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy

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