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Tian, Y.;  Liu, H.;  Wang, M.;  Wang, R.;  Yi, G.;  Zhang, M.;  Chen, R. STAT3 and NRF2 in Tumors. Encyclopedia. Available online: https://encyclopedia.pub/entry/39705 (accessed on 14 September 2024).
Tian Y,  Liu H,  Wang M,  Wang R,  Yi G,  Zhang M, et al. STAT3 and NRF2 in Tumors. Encyclopedia. Available at: https://encyclopedia.pub/entry/39705. Accessed September 14, 2024.
Tian, Yanjun, Haiqing Liu, Mengwei Wang, Ruihao Wang, Guandong Yi, Meng Zhang, Ruijiao Chen. "STAT3 and NRF2 in Tumors" Encyclopedia, https://encyclopedia.pub/entry/39705 (accessed September 14, 2024).
Tian, Y.,  Liu, H.,  Wang, M.,  Wang, R.,  Yi, G.,  Zhang, M., & Chen, R. (2023, January 04). STAT3 and NRF2 in Tumors. In Encyclopedia. https://encyclopedia.pub/entry/39705
Tian, Yanjun, et al. "STAT3 and NRF2 in Tumors." Encyclopedia. Web. 04 January, 2023.
STAT3 and NRF2 in Tumors
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Signal transducer and activator of transcription 3 (STAT3) and nuclear factor erythroid-derived 2-like 2 (NRF2, also known as NFE2L2), are two of the most complicated transcription regulators, which participate in a variety of physiological processes. Numerous studies have shown that they are overactivated in multiple types of tumors. Interestingly, STAT3 and NRF2 can also interact with each other to regulate tumor progression. Hence, these two important transcription factors are considered key targets for developing a new class of antitumor drugs.

signal transduction STAT3 NRF2

1. Introduction

Signal transducer and activator of transcription 3 (STAT3) belongs to the STAT family, which includes STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6, and mediates signal transduction from the cell membrane to the nucleus in multiple intracellular and extracellular activities [1][2]. As a crucial transcription factor, STAT3 exerts a vital role on all STAT proteins. As it is essential for early development, it gets involved in regulating the transcription of a good many crucial genes related to cell proliferation, differentiation, apoptosis, survival, angiogenesis, inflammation, immunity, and metastasis, thereby participating in various physiological and pathological processes [3][4][5]. There is mounting evidence showing that STAT3 plays a crucial role in various diseases, such as cancer [6][7][8], cerebrovascular diseases [9][10], cardiovascular diseases [11][12], and obesity [13].
The STAT3 gene is located on chromosome 17q21 [14][15]. The STAT3 protein consists of 770 amino acids and has six conserved domains. The amino-terminal domain (NTD) of STAT3 performs multiple functions, including protein–protein interactions, cooperative DNA binding, and nuclear translocation [16]. STAT3 interacts with other transcription factors and regulatory proteins via coiled-coil domain (CCD) [17]. The DNA-binding domain (DBD) facilitates STAT3 interactions with target genes. STAT3 dimerization is formed via the Src homology-2 (SH2) domain by identifying phosphorylated Tyr-705 of another STAT monomer [17]. The phosphorylation of serine sites on the C-terminal transcription activation domain (TAD) promotes the assembly of STAT3 with other transcriptional activators [17][18][19]. The structure of the STAT3 protein determines its special functions, which lays the foundation for signal transduction.
Nuclear factor erythroid-derived 2-like 2 (NRF2) possesses a unique Cap ‘n’ Collar (CNC) motif followed by a basic leucine zipper (bZip), which belongs to the CNC transcription factor family. Human NRF2 contains seven highly conserved domains, namely NRF2-ECH (erythroid cell-derived protein with CNC homology) homology and (Neh) 1–Neh7; each domain has its own unique function. A bZip DNA-binding domain and a heterodimerization domain together form the Neh1 domain, which enables DNA-binding to the antioxidant response element (ARE) and the dimerization of NRF2 with small musculoaponeurotic fibrosarcoma (sMAF) proteins [20]. Neh2 is a negative regulatory domain of NRF2, which is crucial for Kelch-like ECH-associated protein 1 (KEAP1)-mediated repression of NRF2 [21]. The C-terminal Neh3 domain acting in parallel with the Neh4 and Neh5 domains has a transactivation-like activity to activate the transcription of NRF2 target genes [22][23]. The Neh6 domain includes two binding sites for β-transducin repeat-containing protein (β-TrCP), DSGIS, and DSAPGS, leading to glycogen synthase kinase 3 beta (GSK3β)-mediated NRF2 degradation in a KEAP1-independent manner [24][25]. Finally, Neh7 contains a domain that mediates a direct interaction between NRF2 and the DBD of retinoid X receptor α (RXRα), which suppresses the transcriptional activity of NRF2 by inhibiting the recruitment of coactivators to Neh4 and Neh5 domains [26].

2. Intricacies of NRF2 Regulation in the Tumor Microenvironment

2.1. NRF2 Signaling Pathway

Under normal conditions, NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-cullin 3 (CUL3)-ring box 1 (RBX1) complex, the β-TrCP-S-phase kinase-associated protein 1 (SKP1)-CUL1-RBX1 complex, and the Hmg-CoA reductase degradation protein 1 (HRD1) [27][28][29][30]. However, when the organism is exposed to endogenous and environmental stresses, NRF2 degradation is interrupted by the inhibition of the UPS, and newly translated NRF2 translocates to the nucleus, binds to sMAF proteins, and transcribes ARE-driven genes. The extensive cytoprotective genes regulated by NRF2 are crucial for suppressing the oxidative, proteotoxic, and metabolic stresses which facilitate malignant transformation. The transient activation of NRF2 during stress is beneficial to health, while a sustained activation of NRF2 has detrimental effects.

2.1.1. Canonical Activation of NRF2

A large body of evidence shows that KEAP1 has become a crucial regulator of the NRF2-mediated signaling pathway. It is generally believed that KEAP1 can function as a molecular switch to sense the imbalance in redox homeostasis and turn on or off the NRF2 signaling pathway [31][32]. Under general conditions, the activity of NRF2 is negatively regulated by KEAP1. During stress, NRF2 upregulation can be induced by oxidative or electrophilic modification of KEAP1 cysteines (i.e., Cys151), which suppresses the formation of the NRF2–KEAP1 complex and results in diminished NRF2 ubiquitination, thereby initiating the canonical NRF2 signaling pathway [33][34][35][36]. Thus, newly translated NRF2 translocates to the nucleus, binds to sMAF proteins, and transcribes ARE-regulated cytoprotective target genes to maintain redox homeostasis [20]. When redox homeostasis is restored, KEAP1 travels into the nucleus to dissociate NRF2 from the ARE and returns NRF2 to the cytosol for ubiquitination and degradation to inhibit the sustained activation of NRF2 [37]. This pattern of NRF2-activation regulation is an immediate consequence of oxidative or electrophilic stresses and is referred to as “canonical activation”. In terms of chemoprevention, NRF2 has been shown to be activated via the canonical mode by various dietary compounds or synthetic chemicals [38]. The treatment strategies for many diseases, including cancer, are based on utilizing the protective capacity of the NRF2 response, which is achieved by transient NRF2 activation via oxidative or electrophilic modification of KEAP1 [39][40][41][42]. Therefore, the canonical activation of NRF2 is crucial to switch on the detoxification of harmful carcinogens and relieve excessive stress to avoid malignant transformation.

2.1.2. Non-Canonical Activation of NRF2

Another important pathway during stress is the autophagy-lysosome pathway, a highly regulated cellular degradation pathway which is responsible for removing damaged, degenerative, and aging proteins and organelles, such as oxidatively damaged proteins and dysfunctional mitochondria. Autophagy dysfunction leads to the accumulation of pathogenic proteins and organelles, which is the root cause of many diseases, including metabolic disorders, neurodegenerative diseases, infectious diseases, cardiovascular diseases, and cancer [43][44]. To some extent, autophagy pathway dysfunction is associated with NRF2 activation. For instance, several studies have found that NRF2 can be activated through autophagy inhibition in a p62-dependent but Keap1-Cys151-independent manner, which is known as “non-canonical activation” [45][46][47][48]. Autophagy dysfunction has been shown to induce the accumulation of p62, a selective autophagy adaptor, which leads to the sequestration and loss of function of numerous binding partners, including KEAP1 [45][49][50]. p62 interacts directly with KEAP1 through its KEAP1-interacting region (KIR), which contains a DPSTGE motif similar to the ETGE motif in NRF2 for KEAP1 binding [47][51]. The KEAP1 sequestration by p62 stabilizes NRF2, which can initiate the transcription of target genes, including p62, creating a positive feedback loop and prolonging NRF2 activation [49]. However, the excessive accumulation of p62 induces sustained NRF2 activation, which facilitates the formation and development of tumors [52]. Deletion of p62 consistently inhibits NRF2 activation and arsenic-induced malignant transformation of human keratinocytes [53]. The relationship between the non-canonical activation of NRF2 and carcinogenesis must be thoroughly investigated to identify a potential target for cancer treatment or prevention.

2.2. Dual Roles of NRF2 in Tumor

NRF2 has traditionally been considered a tumor suppressor since the NRF2–KEAP1 signaling pathway is an essential cell protection mechanism that can defend against oxidative/electrophilic stresses and promote cell survival. The activation of the NRF2 pathway induced by natural compounds is an effective chemoprevention strategy [54]. Moreover, NRF2-deficient mice are more susceptible to develop cancer, and NRF2 deficiency is associated with cancer metastasis [55][56][57][58].
Transient activation of NRF2 during stress is beneficial to normal cells, whereas hyperactivation of NRF2 facilitates the survival of normal as well as malignant cells. Recent evidence suggests that the “dark” side of NRF2 may be mediated by excessive accumulation of p21 and p62 via disruption of NRF2–KEAP1 interactions [45][59]. In addition, NRF2 can exert a significant action of chemoresistance, inhibiting drug accumulation in cancer cells, and thereby contributing to survival of cancer cells. Considering the pro-tumorigenic effect of NRF2 in cancer cells, pharmacological suppression of the NRF2 pathway will emerge as a promising area of cancer research. Several groups have identified many NRF2 pharmacological inhibitors, such as brusatol, halofuginone, luteolin, and procyanidin [60][61][62][63]. However, there is currently no FDA-approved drug to suppress NRF2 activation. Therefore, extensive research is required to identify drugs that can prevent and treat cancer.

3. Crosstalk between the STAT3 and NRF2 Signaling Pathways in the Tumor Microenvironment

Interestingly, the STAT3 and NRF2 signaling pathways can interact with each other (Figure 2), which undoubtedly increases the complexity of their signal transduction and the diversity of drug treatment targets. There is increasing evidence that STAT3 and NRF2 have synergistic effects in cancer cells [64][65]. Wu et al. found that IL-6 secreted by pancreatic stellate cell (PSC)-induced EMT phenotypes and gene expression in Panc-1 cells by activating STAT3, which in turn induced the expression of NRF2 and its target genes to mediate EMT [66]. EMT is a process where epithelial cells lose their cell–cell adhesion and apical-basolateral polarity and obtain mesenchymal features [67][68]. Numerous studies indicate that several metastatic cancers are caused by IL-6-induced EMT events [67][68][69]. Results from Wu et al. show that PSC-secreted IL-6 binds to its receptor and activates JAK/STAT3 signaling, which then triggers intracellular NRF2 signaling and its downstream EMT-related transcription factors to drive the expression of EMT-related marker genes, thereby inducing EMT in Panc-1 cells [66]. This showed that the IL-6/STAT3/NRF2 signaling pathway might play a role in the progression of pancreatic ductal adenocarcinoma (PDAC) [66]. Another study found that the expression levels of both STAT3 and NRF2 were increased in HT-29 colon cancer cells, but when treated with the combination of 5-fluorouracil (5-FU) and stattic, the level of NRF2 decreased after the reduction of STAT3 expression [70]. It may be assumed that the effect of 5-FU may inhibit STAT3 and NRF2 signal transduction by blocking IL-6. The specific mechanism still needs a great quantity of research.
Moreover, in osteosarcoma cells, overactivation of STAT3/NRF2 signaling can lead to cisplatin resistance by increasing glutathione peroxidase 4 (GPX4) activity, thereby suppressing ferroptosis [65]. However, when BP-1-102, a STAT3 inhibitor, was used, the expression levels of NRF2 and GPX4 were strikingly decreased, which reactivated ferroptosis and enhanced the sensitivity of osteosarcoma cells to cisplatin [65].
Furthermore, both Nrf2 and STAT3 are overexpressed in breast cancer, especially in basal-like breast cancer (BLBC). Kim et al. found that NRF2 can form a stable complex with Y705 phosphorylated dimeric form of STAT3, which may accelerate the progression of breast cancer by inducing IL-23A expression [71]. IL-23A is significantly overexpressed in almost half of BLBC patients. It is worth noting that the survival rate of breast cancer patients with high levels of IL-23A mRNA is worse than that of patients with no or low expression of IL-23A mRNA [71]. IL-23 is a common proinflammatory cytokine which mainly exists in activated macrophages, dendritic cells, and keratinocytes in healthy skin [72]. However, recent studies have shown that IL-23 is also involved in tumor growth and metastasis by directly binding to the IL-23 receptor, which is expressed in a variety of in inflammation-related malignant tumors, including breast cancer [73]. The STAT3–NRF2 complex located in the nucleus where it binds to the promoter region of the IL-23A gene and induces its transcription. The protein products of IL-23A can bind to their receptors in BLBC cells in an autocrine manner, which will amplify the intracellular signals for breast cancer cell proliferation, migration, metastasis, etc. [71]. In view of this, the STAT3/NRF2-IL-23A axis can emphasize the importance of subtype-specific molecular pathways, which can be a potential therapeutic target.

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