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Open AccessArticle

Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

1
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway
2
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway
3
Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, 0424 Oslo, Norway
4
Department of Informatics, University of Oslo, 0316 Oslo, Norway
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1719; https://doi.org/10.3390/cancers12071719
Received: 25 May 2020 / Revised: 20 June 2020 / Accepted: 24 June 2020 / Published: 28 June 2020
(This article belongs to the Section Molecular Cancer Biology)
The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process. View Full-Text
Keywords: melanoma; melanocyte transformation; MITF; MC1R; AXL inhibitor; familial melanoma melanoma; melanocyte transformation; MITF; MC1R; AXL inhibitor; familial melanoma
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Lavelle, T.J.; Alver, T.N.; Heintz, K.-M.; Wernhoff, P.; Nygaard, V.; Nakken, S.; Øy, G.F.; Bøe, S.L.; Urbanucci, A.; Hovig, E. Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes. Cancers 2020, 12, 1719.

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