The AP-1 transcription factor FOSL1 causes melanocyte reprogramming and transformation

The MAPK pathway is activated in the large majority of melanomas and is the subject of several therapeutic approaches. Under normal conditions, it quickly raises the so-called immediate early response, which encompasses the transient transcription of several genes belonging to the AP-1 transcription factor family. Under pathological conditions such as consistent MAPK pathway overactivation due to oncogenic alterations occurring in melanoma, these genes are permanently expressed. The consequences of a permanent expression of these genes are currently unknown. Here, we show that FOSL1 is the main immediate early AP-1 member induced by melanoma oncogenes. We first examined its role in established melanoma cells, and found that FOSL1 is involved in melanoma migration as well as cell proliferation and anoikis-independent growth, which is mediated by the gene product of its target gene HMGA1, a multipotent chromatin modifier. As FOSL1 expression is increased in melanomas compared to nevi, we investigated the effect of enhanced FOSL1 expression on melanocytes and found that FOSL1 is able to reprogram them by shifting the balance between MITF and AXL and re-enforcing pro-tumorigenic trancription factors MYC, E2F3 and AP-1. This results in the enhancement of growth-promoting processes such as ribosome biogenesis and pyrimidine metabolism and eventually causes the transformation of melanocytes into malignant tumors.