knock down of NRF2 in melanoma

The transcription factor NRF2 is closely connected to therapy resistancein tumors like lung and bladder cancer, where it is frequently constitutivelyactivated due to mutations in NRF2 or its inhibitory interaction partner KEAP1.In melanoma, such mutations are rare, but NRF2 might be activated by endogenouseffectors in this tumor entity. Here, we investigate modes of NRF2 activationand the biological role of NRF2 in melanoma.RNA sequencing revealed that depletion of NRF2led to the expected repression of antioxidant genes. However, the strongesteffect of NRF2 was the regulation of the gene PTGS2, encodingcyclooxygenase 2 (COX2), which is known to generate melanoma immune toleranceby elevating prostaglandin E2 levels. Furthermore, NRF2 suppressed the activityof MITF and the expression of pigmentation-relevant genes particularly in cellswith low endogenous MITF expression. By repressing MITF, NRF2 was also involvedin keeping up features of dedifferentiated cells, including the expression ofthe receptor tyrosine kinase EGFR.