TY - JOUR A1 - Friedmann Angeli, José Pedro A1 - Meierjohann, Svenja T1 - NRF2‐dependent stress defense in tumor antioxidant control and immune evasion JF - Pigment Cell & Melanoma Research N2 - The transcription factor NRF2 is known as the master regulator of the oxidative stress response. Tumor entities presenting oncogenic activation of NRF2, such as lung adenocarcinoma, are associated with drug resistance, and accumulating evidence demonstrates its involvement in immune evasion. In other cancer types, the KEAP1/NRF2 pathway is not commonly mutated, but NRF2 is activated by other means such as radiation, oncogenic activity, cytokines, or other pro‐oxidant triggers characteristic of the tumor niche. The obvious effect of stress‐activated NRF2 is the protection from oxidative or electrophilic damage and the adaptation of the tumor metabolism to changing conditions. However, data from melanoma also reveal a role of NRF2 in modulating differentiation and suppressing anti‐tumor immunity. This review summarizes the function of NRF2 in this tumor entity and discusses the implications for current tumor therapies. KW - immune evasion KW - KEAP1 KW - Nrf2 KW - oxidative stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224536 VL - 34 IS - 2 SP - 268 EP - 279 ER - TY - JOUR A1 - Kreß, Julia Katharina Charlotte A1 - Jessen, Christina A1 - Marquardt, André A1 - Hufnagel, Anita A1 - Meierjohann, Svenja T1 - NRF2 enables EGFR signaling in melanoma cells JF - International Journal of Molecular Sciences N2 - Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype. Here, we describe that the transcription factor NRF2, the master regulator of the oxidative and electrophilic stress response, mediates the expression and activation of EGFR in melanoma by elevating the levels of EGFR as well as its ligands EGF and TGFα. ChIP sequencing data show that NRF2 directly binds to the promoter of EGF, which contains a canonical antioxidant response element. Accordingly, EGF is induced by oxidative stress and is also increased in lung adenocarcinoma and head and neck carcinoma with mutationally activated NRF2. In contrast, regulation of EGFR and TGFA occurs by an indirect mechanism, which is enabled by the ability of NRF2 to block the activity of the melanocytic lineage factor MITF in melanoma. MITF effectively suppresses EGFR and TGFA expression and therefore serves as link between NRF2 and EGFR. As EGFR was previously described to stimulate NRF2 activity, the mutual activation of NRF2 and EGFR pathways was investigated. The presence of NRF2 was necessary for full EGFR pathway activation, as NRF2-knockout cells showed reduced AKT activation in response to EGF stimulation compared to controls. Conversely, EGF led to the nuclear localization and activation of NRF2, thereby demonstrating that NRF2 and EGFR are connected in a positive feedback loop in melanoma. In summary, our data show that the EGFR-positive melanoma phenotype is strongly supported by NRF2, thus revealing a novel maintenance mechanism for this clinically challenging melanoma subpopulation. KW - EGFR KW - NRF2 KW - NFE2L2 KW - KEAP1 KW - MITF-low KW - TGF-alpha KW - EGF KW - NSCLC KW - HNSC Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260222 SN - 1422-0067 VL - 22 IS - 8 ER -