Transcriptional control of phenotype in melanoma

Melanoma is the most aggressive and deadly type of skin cancer, mainly as a consequence of its high metastatic capacity and refractoriness to treatment. Over recent years increasing evidence suggests that the intra-tumour microenvironment can drive cells to adopt invasive and drug-resistant phenotypes that play a key role in disease progression. Understanding how phenotypic heterogeneity is generated, and the molecular mechanisms underpinning the acquisition of invasive or drug-resistant states is key to the development of more effective therapies. Current evidence suggests an important role for the micropththalmia-associated transcription factor MITF in the development of phenotypic heterogeneity in melanoma. Yet how MITF is regulated and how it controls melanoma biology remains poorly characterised. Here we show that activating transcription factor 4 (ATF4), whose expression is induced via a translational switch that occurs under microenvironment stresses frequently found in tumours such as nutrient deprivation or hypoxia, has the potential to directly supress MITF expression and also directly target a repertoire of well-characterised and novel MITF target genes. In addition, ATF4 also directly binds and has the potential to activate expression of novel target genes linked to invasiveness/metastasis or with a cytoprotective role. Our results therefore suggest that in response to a stressful intra-tumour microenvironment the induction of ATF4 provides a potentially reversible mechanism for the generation of phenotype heterogeneity in melanoma leading to the acquisition of metastatic and/or drugresistant capacities in specific subpopulations of cells.