Enhancer Remodeling Promotes Tumor-Initiating Activity in NRF2-Activated Non-Small Cell Lung Cancers

Okazaki, Kazuyuki; Anzawa, Hayato; Liu, Zun; Ota, Nao; Kitamura, Hiroshi; Onodera, Yoshiaki; Alam, Md. Morshedul; Matsumaru, Daisuke; Suzuki, Takaya; Katsuoka, Fumiki; Tadaka, Shu; Motoike, Ikuko N.; Watanabe, Mika; Sakurada, Akira; Okada, Yoshinori; Yamamoto, Masayuki; Suzuki, Takashi; Kinoshita, Kengo; Sekine, Hiroshi; Motohashi, Hozumi

doi:10.1101/2020.04.24.060798

Cited by 9 publications

(12 citation statements)

References 74 publications

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“…One of the approaches to identify such targets is to explore NRF2 downstream effectors unique to NRF2‐activated cancers. NOTCH3 was identified as a unique NRF2‐target gene in NRF2‐activated LUAD and turned out to be an advantageous therapeutic target because NOTCH3, being a membrane protein, can be inhibited by acting on its extracellular domains, thereby avoiding the elevated detoxification capacity of NRF2‐activated cancer cells [42].…”

Section: Discussionmentioning

confidence: 99%

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Genetic, metabolic and immunological features of cancers with NRF2 addiction

2022

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Nuclear factor erythroid‐derived 2‐like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumourigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant cancer cells. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2‐activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.

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Section: Discussionmentioning

confidence: 99%

“…NRF2 and CEBPB cooperate also in promoting the tumour‐initiating activity of NSCLC cells by inducing NOTCH3 expression [42] (Fig. 2), which likely contributes to the higher incidence of postoperative recurrence of NRF2‐activated NSCLC [43].…”

Section: Malignant Phenotypes Driven By Persistent Nrf2 Activation In...mentioning

confidence: 99%

Genetic, metabolic and immunological features of cancers with NRF2 addiction

2022

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“…Under physiological conditions, Nrf2 is localized primarily in the cytoplasm and bound by Kelch-like ECH-associated protein 1 (Keap1) that hinders the activation of Nrf2 [26]. In response to oxidative stress, Nrf2 is disengaged from its binding to Keap1 and translocated into the nucleus, where Nrf2 potentiates the transcription of antioxidant response elements (AREs) and induces a battery of antioxidant proteins [27]. Nrf2 pathway plays a crucial role in protecting human melanocytes from oxidative stress as demonstrated by our previous studies [4,5,28,29].…”

Section: Discussionmentioning

confidence: 99%

Folic Acid Protects Melanocytes from Oxidative Stress via Activation of Nrf2 and Inhibition of HMGB1

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Vitiligo is a cutaneous depigmentation disease due to loss of epidermal melanocytes. Accumulating evidence has indicated that oxidative stress plays a vital role in vitiligo via directly destructing melanocytes and triggering inflammatory response that ultimately undermines melanocytes. Folic acid (FA), an oxidized form of folate with high bioavailability, exhibits potent antioxidant properties and shows therapeutic potential in multiple oxidative stress-related diseases. However, whether FA safeguards melanocytes from oxidative damages remains unknown. In this study, we first found that FA relieved melanocytes from H2O2-induced abnormal growth and apoptosis. Furthermore, FA enhanced the activity of antioxidative enzymes and remarkably reduced intracellular ROS levels in melanocytes. Subsequently, FA effectively activated nuclear factor E2-related factor 2 (Nrf2) pathway, and Nrf2 knockdown blocked the protective effects of FA on H2O2-treated melanocytes. Additionally, FA inhibited the production of proinflammatory HMGB1 in melanocytes under oxidative stress. Taken together, our findings support the protective effects of FA on human melanocytes against oxidative injury via the activation of Nrf2 and the inhibition of HMGB1, thus indicating FA as a potential therapeutic agent for the treatment of vitiligo.

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“…High C/EBPβ expression is associated with tumour aggressiveness and poor outcomes 7–11 . C/EBPβ drives the progression of non‐alcoholic fatty liver to hepatocellular carcinoma, 12 glioblastoma growth in vivo , 13 tumour initiation, and malignancy in non‐small cell carcinoma (lung cancer) 14 and skin cancers 15 …”

Section: Introductionmentioning

confidence: 99%

C/EBPβ promotes the expression of atrophy‐inducing factors by tumours and is a central regulator of cancer cachexia

AlSudais

Rajgara

Saleh

et al. 2022

J cachexia sarcopenia muscle

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Background CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia-inducing tumours, C/EBPβ is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C/EBPβ induces the expression of many secreted factors, including cytokines. Because tumour-secreted factors drive cachexia and aggressive tumours have higher expression of C/EBPβ, we examined a potential role for C/EBPβ in the expression of tumour-derived cachexia-inducing factors. Methods We used gain-of-function and loss-of-function approaches in vitro and in vivo to evaluate the role of tumour C/EBPβ expression on the secretion of cachexia-inducing factors. ResultsWe report that C/EBPβ overexpression up-regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (À31%, P < 0.05) and myotube maturation [À38% (fusion index) and À25% (myotube diameter), P < 0.05]. We find that knockdown of C/EBPβ in cachexia-inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, P < 0.0001) and myotube diameter (+90%, P < 0.0001) in conditioned medium experiments and, in vivo, prevents muscle wasting (À51% for small myofibres vs. controls, P < 0.01; +140% for large myofibres, P < 0.01). Conversely, overexpression of C/EBPβ in non-cachectic tumours converts their secretome into a cachexia-inducing one, resulting in reduced myotube diameter (À41%, P < 0.0001, EL4 model) and inhibition of differentiation in culture (À26%, P < 0.01, EL4 model) and muscle wasting in vivo (+98% small fibres, P < 0.001; À76% large fibres, P < 0.001). Comparison of the differently expressed transcripts coding for secreted proteins in C/EBPβ-overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C/EBPβ-regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up-regulated by C/EBPβ. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (À33 to À36% for myotube diameter, P < 0.01). Conclusions We find that C/EBPβ is necessary and sufficient to induce the secretion of cachexia-inducing factors by cancer cells and loss of C/EBPβ in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C/EBPβ as a central regulator of cancer cachexia and an important therapeutic target.

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Enhancer Remodeling Promotes Tumor-Initiating Activity in NRF2-Activated Non-Small Cell Lung Cancers

Cited by 9 publications

References 74 publications

Genetic, metabolic and immunological features of cancers with NRF2 addiction

Genetic, metabolic and immunological features of cancers with NRF2 addiction

Folic Acid Protects Melanocytes from Oxidative Stress via Activation of Nrf2 and Inhibition of HMGB1

C/EBPβ promotes the expression of atrophy‐inducing factors by tumours and is a central regulator of cancer cachexia

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