Abstract
The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
Highlights
Cutaneous melanoma is a tumor entity with the ability to quickly adapt to various stressors
As BRAFV600E is the most frequent mutation in melanoma [3, 22, 23], and BRAF and RAS oncogenes were described as potential inducers of NRF2 [24], we tested the effect of BRAFV600E expression on NRF2 in melanocytes
We describe the critical role of NRF2 in melanoma dedifferentiation, PTGS2 expression and the corresponding suppression of innate immune response genes
Summary
Cutaneous melanoma is a tumor entity with the ability to quickly adapt to various stressors Due to their anatomic location and biology, melanomas and their non-malignant precursors, the melanocytes, encounter numerous sources of stress. The melanoma oncogenes BRAF or NRAS [6, 7], as well as hypoxia, nutrient deprivation, or immune mediators are common stress triggers during melanoma development and maintenance [8,9,10,11]. Adaptation to these constant threats requires efficient stress responses, which allow tumors to survive under the new, often hostile, conditions. The recent observation that NRF2 is involved in transcriptional activation of PDL1 [21] implies that NRF2 might play a larger role in melanoma than previously anticipated
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