SOX2 modulates levels of MITF in normal human melanocytes, and melanoma lines in vitro.
Pigment Cell Melanoma Res
Melanocytes, the pigment cells of the skin, originate during development from neural crest cells, a transient, plutipotent and highly migratory population of cells. Genetic mutations in melanocytes may result in melanoma, one of the most malignant and invasive type of tumors whose its incidence has been increasing at an alarming high rate in recent years. MITF is a transcription factor playing critical roles in both melanocytes and melanoma cell biology. It controls the molecular machinery dedicated to the production of melanin pigments and, more importantly, according to its levels of expression it can promote malignant proliferation (low levels), differentiation (high levels) or cell death (no expression) of melanoma cells. The transcription factor SOX2 is a master regulator of embryonic stem cell and neural precursor cell biology. Recently, It has been suggested that SOX2 also plays a role in both melanocyte development and melanoma progression. In fact, It has been noted that this pluripotency factor is re-expressed in approximately 45% and 40% of, respectively, primary and metastatic melanomas. Furthermore, several studies suggest that SOX2 functions as an oncogene in this type of tumor. In this work we explored the connection between this two important regulators of melanocytes and melanoma biology. We found that SOX2 functions as a modulator of MITF expression. Endogenous levels of SOX2 are in fact required to sustain the expression of MITF in all the cell lines analyzed. Interestingly however, overexpression of SOX2 also reduces the levels of MITF expression in at least one of the melanoma lines analyzed, thus suggesting a non-linear type of regulation. Overall, our work suggest that SOX2 is able to modulate the expression of MITF which, in turn, might contribute to the oncogenic function of SOX2 in this type of cancer. In the light of our results, it is in fact tempting to speculate that the SOX2 positive cells present within a melanoma tumor might represent the cells with low expresssion of MITF, suggested to be the proliferating cells within the lesion.