Oncogenic mutations in <i>KEAP1</i> disturbing inhibitory Nrf2‐Keap1 interaction: Activation of antioxidative pathway in papillary thyroid carcinoma

Danilovic, Débora Lucia Seguro; Mello, Evandro Sobroza de; Frazzato, Eliana Salgado Turri; Wakamatsu, Alda; Jorge, Alexander A L; Hoff, Ana O.; Marui, Suemi

doi:10.1002/hed.25105

Cited by 15 publications

(19 citation statements)

References 39 publications

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“…KEAP1 , and NFE2L2 somatic mutations have been identified and characterized in various human cancers, including lung, liver, renal, and squamous cell cancers, leukemia, and others (40). Sequencing of PTC samples did not reveal any mutations in NFE2L2 (and particularly in its known mutational hotspot in exon 2 that encodes one of the domains responsible for the binding to Keap1) (42–44); however, several different mutations were identified in KEAP1 , albeit at a very low overall frequency (43, 44). The different somatic mutations identified in KEAP1 in thyroid tumors are shown in Figure 3, Table 1.…”

Section: Thyroid Carcinomasmentioning

confidence: 92%

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer

et al. 2019

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The Keap1/Nrf2 pathway is a key mediator of general redox and tissue-specific homeostasis. It also exerts a dual role in cancer, by preventing cell transformation of normal cells but promoting aggressiveness, and drug resistance of malignant ones. Although Nrf2 is well-studied in other tissues, its roles in the thyroid gland are only recently emerging. This review focuses on the involvement of Keap1/Nrf2 signaling in thyroid physiology, and pathophysiology in general, and particularly in thyroid cancer. Studies in mice and cultured follicular cells have shown that, under physiological conditions, Nrf2 coordinates antioxidant defenses, directly increases thyroglobulin production and inhibits its iodination. Increased Nrf2 pathway activation has been reported in two independent families with multinodular goiters due to germline loss-of-function mutations in KEAP1 . Nrf2 pathway activation has also been documented in papillary thyroid carcinoma (PTC), due to somatic mutations, or epigenetic modifications in KEAP1 , or other pathway components. In PTC, such Nrf2-activating KEAP1 mutations have been associated with tumor aggressiveness. Furthermore, polymorphisms in the prototypical Nrf2 target genes NQO1 and NQO2 have been associated with extra-thyroidal extension and metastasis. More recently, mutations in the Nrf2 pathway have also been found in Hürthle-cell (oncocytic) thyroid carcinoma. Finally, in in vitro , and in vivo models of poorly-differentiated, and undifferentiated (anaplastic) thyroid carcinoma, Nrf2 activation has been associated with resistance to experimental molecularly-targeted therapy. Thus, Keap1/Nrf2 signaling is involved in both benign and malignant thyroid conditions, where it might serve as a prognostic marker or therapeutic target.

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Section: Thyroid Carcinomasmentioning

confidence: 92%

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer

et al. 2019

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“…Nrf2 accumulates and enters the nucleus and induces its target genes via specific binding sequences called antioxidant response elements (AREs). In the last few years, a role of Nrf2 in thyroid physiology and pathophysiology has emerged [ 7 ]; Nrf2 upregulates Tg transcription [ 2 ] through AREs in a Tg enhancer [ 2 , 8 ], downregulates Tg iodination [ 2 ], and is activated in response to iodide exposure [ 2 , 9 ], as well as in thyroid carcinomas [ 10 , 11 , 12 ]. The Nrf2 pathway is of high medical interest due to its druggable nature, and Nrf2 inducers have been tested in clinical trials for cancer chemoprevention, chronic kidney disease, neurodegenerative diseases, and diabetes [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Chartoumpekis

Ziros

Georgakopoulos-Soares

et al. 2020

Antioxidants

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Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC.

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“…These findings shed light on the biological origin of LCNEC and might have important implications for the clinical management of these aggressive tumors [143]. Notably, KEAP1 missense or nonsense mutations have also been reported in malignant melanoma [144] and hepatocellular [145], papillary thyroid [146], and endometrial carcinomas [147] as well as gall bladder [148], breast [149, 150], cervical [151], and ovarian cancers [152]. In all the cases, the inactivation of KEAP1 was paralleled by NRF2 overexpression that in turn promoted an aggressive phenotype characterized by enhanced antioxidant capacity and decreased sensitivity to chemotherapeutics.…”

Section: Nrf2/keap1 Prooncogenic Activity In Cancer: Causes and Comentioning

confidence: 99%

Potential Applications of NRF2 Inhibitors in Cancer Therapy

Panieri¹,

Saso²

2019

Oxidative Medicine and Cellular Longevity

159

140

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The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

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Oncogenic mutations in KEAP1 disturbing inhibitory Nrf2‐Keap1 interaction: Activation of antioxidative pathway in papillary thyroid carcinoma

Abstract: We identified mutations in KEAP1 associated with Nrf2 overexpression in PTC. Mutations favored disruption of inhibitory interaction Nrf2-Keap1 to enable increased antioxidant Nrf2 activity, possibly with prognostic consequences.

Cited by 15 publications

References 39 publications

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer

Keap1/Nrf2 Signaling: A New Player in Thyroid Pathophysiology and Thyroid Cancer

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Potential Applications of NRF2 Inhibitors in Cancer Therapy

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