NRF2 Enables EGFR Signaling in Melanoma Cells

Abstract

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.

Proteomic Changes in the Monolayer and Spheroid Melanoma Cell Models of Acquired Resistance to BRAF and MEK1/2 Inhibitors

“…We also observed activation in the NRF2 signaling and glutathione redox pathways in PLX/AZD-resistant spheroids (Table ), which may also contribute to temozolomide resistance, as demonstrated in orthotopic glioma xenograft models . NRF2 has also been implicated in regulating EGFR expression in drug-resistant melanoma . In terms of drug efflux, several ABC transporters, ABCC1 and ABCD1, were upregulated in the PLX/AZD-resistant spheroids (Table ) and have also been implicated in a multidrug-resistant phenotype …”

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…More recently, high Nrf2 expression was found in glioma tissues compared with non-glioma specimens and the natural compound corilagin was shown to downregulate Nrf2 expression and to induce apoptosis in glioma models [ 72 ]. Nrf2 was also upregulated in melanoma enhancing tumour malignancy by blocking differentiation and inducing COX2 expression [ 73 ] and promoting EGFR mediated oncogenic signalling [ 74 ]. Alternative splicing mechanisms in the Nrf2 transcript may also contribute to loss of the Keap1 binding domain and Nrf2 hyperactivation.…”

Aloysia Citrodora Essential Oil Inhibits Melanoma Cell Growth and Migration by Targeting HB-EGF-EGFR Signaling

“…A recent study demonstrated that stress-induced NRF2 binds to the ARE in the EGF promoter and leads to elevation of soluble EGF, while simultaneously blocking MITF activity, resulting in derepression of EGFR and TGFA [ 19 ]. This leads to EGFR activation.…”

“…Expression of EGFR in melanoma establishes a pro-metastatic phenotype [ 17 ] that can activate Ras/MAPK, PLCγ1/PKC, Akt, and STAT, which subsequently stimulate cell proliferation, migration, invasion, survival, and differentiation. The receptor tyrosine kinase EGFR is activated in a subset of melanoma cells [ 18 , 19 ] where its expression correlates with poor prognosis in human melanoma [ 20 , 21 ].…”