Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

Abstract

<jats:p>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.</jats:p>

The MC1R r allele does not increase melanoma risk in MITF E318K carriers

“…The interaction between MC1R and MITF , two moderate-risk genes for melanoma, has long been debated in the literature. 17 , 26 , 28 Understanding the interactive relationship between MITF E318K and MC1R RHC variants may be able to help facilitate individualized risk stratification and the customization of screening recommendations. We have shown that RHC alleles and genotypes modified melanoma risk differentially in MITF E318K + and E318K – individuals.…”

“…A recent study in melanocyte cell lines showed that the forced expression of MITF , consistent with the effects of the E318K variant, leads to the development of malignant cells in MC1R genotype R/R cells, while this did not occur in the wt/wt genotype cells. 28 Unfortunately, the study did not explore the impact of forced expression of MITF on other RHC genotypes, such as r/r. Based on findings from our study, it is possible that forced expression of MITF may have a similar impact on cells heterozygous for the R allele and have little to no impact on cells with non-R genotypes (r/r, r/wt and wt/wt).…”

“… 27 A functional study showed that forced expression of MITF leads to the development of malignant cells in MC1R R/R genotypes, while this does not occur in MC1R wt genotypes. 28 There have been no studies investigating how individual MC1R RHC alleles and/or genotypes moderate the risk of developing melanoma in E318K + individuals. We therefore aimed to evaluate whether MC1R RHC alleles and genotypes moderate melanoma risk in MITF E318K + and E318K – cohorts.…”

BRN2 and MITF together impact AXL expression in melanoma

“…[9][10][11] Interestingly, expression of MITF in immortalized melanocytes caused increased expression of AXL. 18 Mechanistically, it appears that neither MITF nor BRN2 directly repress AXL expression. Analysis of the promoter region of AXL and published ChIP-seq data do not show potential binding of either transcription factor.…”

Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment

“…These cancer cells demonstrate a significant ability to self-repair DNA damage and express high levels of proteins involved in the elimination of xenobiotics. The initiation and progression of melanoma are mediated via genetic and epigenetic alterations to the key molecules in multiple signaling pathways, such as the RAS/RAF/MAPK, JNK, PI3K/Akt and Jak/STAT pathways; they are also influenced by the dysregulation of the MITF (Microphthalmia-Associated Transcription Factor) protein [4][5][6][7]. This property of melanoma cells strongly inhibits the effect of chemotherapeutics.…”