1224 POU3F2 is a radioprotector and a tumor suppressor

Abstract

Melanoma is known as a radioresistant tumor. Melanoma is intra-tumorally highly heterogeneous due to its genetic instability and plasticity. This heterogeneity may explain, at least in part, the natural neo and acquired resistance of melanoma against therapies. In a two dimensional biological world, cells may switch from proliferative to invasive, and vice versa. Two transcription factors, MITF and POU3F2, may be of great importance in this switch. POU3F2 is a transcription factor belonging to the Oct family. In vitro studies have shown that POU3F2 is transcriptionally controlled by the Lef/β-catenin complex and indirectly controlled by BRAF. Moreover, the level of POU3F2 mRNA is controlled by miR-211, which is directly induced by MITF. This switch would be modulated by the transcriptional activity of POU3F2 on MITF, but also on other crucial proteins of the melanocyte lineage such as PAX3. In a human melanoma metastasis, it appears that melanoma cells are mainly POU3F2-positive or MITF-positive. However some cells express both or none of these two proteins. Here, we evaluated the importance of POU3F2 during the establishment, the renewal and transformation of melanocytes using genetically modified mouse models, human genetics and cell lines. It appears that POU3F2 is dispensable during the establishment and the renewal of melanocytes. The specific lack of POU3F2 in the melanocyte lineage reveals that this protein is important for melanoma resistance against ionizing irradiation, which consequently results in the disappearance of melanocyte stem cells over time. Moreover, mouse melanoma models relevant for humans were generated, showing that POU3F2 plays an important role during melanoma initiation and can be better used to improve melanoma therapies.