Antitumoral activity induced by peptides from transcription factor Brn-2 in murine and human melanoma

Abstract

The transcription factor Brn-2 (POU3F2 / N-Oct-3) is involved to the normal development of melanocytic lineage, however, when overexpressed it can reactivate signals to an abnormal growth as in melanoma. Moreover, several studies showed that Brn-2 expression is regulated by three major signaling pathways in melanoma, the Wnt/-catenin, MAPK/BRAF and PI3K /Akt pathways.Brn-2 can regulate the levels of MITF, further suppressing the phenotype of melanocytic differentiation and promoting tumor metastasis. Melanoma cells with lower levels of MITF are more invasive, clearly implying Brn-2 in melanoma tumorigenicity and metastasis. However, Brn-2 can also activate the MITF promoter as result of BRAF constitutive activation. Brn-2 is also a T-cadherin and PDE5A suppressor. PDE5A suppression leads to an increase of intracellular Ca2+, stimulating invasion. Furthermore, Brn-2 has been implicated in the regulation of NOTCH pathway, another pathway related to melanoma progression.Thus, we propose in this work that specific inhibitors of Brn-2 could interfere with melanoma growth and the mechanisms of invasion. Peptides from Brn-2 could have different inhibitory effects on the development of melanoma, including competition with the binding site in transcription factor Brn-2 DNA. The effects of these peptides could be related to migration and invasion inhibition, changes in cell cycle and many other processes including apoptosis, autophagy and necroptosis. These peptides will be tested in melanoma cell lines targeting cytotoxic effects that can be helpful to the development of promising anticancer drugs. (AU)