Malignant melanoma is the deadliest form of skin cancer and NRF2 has been proposed as a main regulator of tumor cell malignancy. Still the mechanisms how NRF2 is contributing to melanoma progression are incompletely understood. Here we analyzed the effects of either NRF2 induction or depletion, and we also quantified changes on the whole cell proteome level. Our results showed that inhibition of NRF2 leads to a loss of reactive oxygen species protection, but at the same time to an induction of an epithelial mesenchymal transition (EMT) phenotype and an up‐regulation of the stem cell marker CD44. Additionally, cells devoid of NRF2 showed increased cell viability after treatment with a MYC and a BRAF inhibitor. Importantly, survival upon vemurafenib treatment was dependent on CD44 expression. Finally, analysis of archival melanoma patient samples confirmed a vice versa relationship of NRF2 and CD44 expression. In summary, we recorded changes in the proteome after NRF2 modulation in melanoma cells. Surprisingly, we identified that NRF2 inhibition lead to induction of an EMT phenotype and an increase in survival of cells after apoptosis induction. Therefore, we propose that it is important for future therapies targeting NRF2 to consider blocking EMT promoting pathways in order to achieve efficient tumor therapy.

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BACKGROUNDFor decades, researchers have strived to analyze the process of tumour formation and progression. Despite the immense accumulation of knowledge, cancer still remains one of the biggest burdens of our society today. According to the WHO, nearly one in six deaths worldwide was attributed to cancer in 2020. Hence, it is crucial to revisit and build upon recent achievements to improve our understanding of this disease.One of the most important concepts to describe the growth and spreading of tumour cells in patients over time is the phenotype-switching model. 1 This model was first discovered in melanoma and is also applicable to other tumours. It is based on the idea that tumour cells can exist in two different cellular states. On the one hand, they exhibit a high proliferative activity with a high rate of glycolysis, but low migrative and invasive capacity. On the other hand, cells can exist in a state hallmarked by up-regulation of migrative and invasive behaviour with inflammation-related pathways being increased. Therefore, increasing evidence supports the idea that tumours progress to metastasis by dynamically switching from a local, proliferative state to a highly migrative state, whichThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.