Brn-2 Expression Controls Melanoma Proliferation and Is Directly Regulated by β-Catenin

Abstract

Constitutive activation of the Wnt/β-catenin signaling pathway is a notable feature of a large minority of cases of malignant melanoma, an aggressive and increasingly common cancer. The identification of target genes downstream from this pathway is therefore crucial to our understanding of the disease. The POU domain transcription factor Brn-2 has been implicated in control of proliferation and melanoma survival, and its expression is strongly upregulated in melanoma. We show here that in vivo Brn-2 is expressed in melanocytes but not in embryonic day 11.5 melanoblasts and that its expression is directly controlled by the Wnt/β-catenin signaling pathway in melanoma cell lines and in transgenic mice. Moreover, silent interfering RNA-mediated inhibition of Brn-2 expression in melanoma cells overexpressing β-catenin results in significantly decreased proliferation. These results, together with the observation that BRAF signaling also induces Brn-2 expression, reveal that Brn-2 is a focus for the convergence of two key melanoma-associated signaling pathways that are linked to cell proliferation.

We thank Rudi Grosschedl for the β-catenin expression vector, Kathy Jones for anti-LEF1 antibody, Marshall Nirenberg for a Brn-2 genomic clone, Ian Hart for the VUP melanoma cell line, Jean-Jacques Panthier for the newborn W/W-lacZ pups, and Hans Clevers for the Lef1 expression vector.

This work was supported by the Association for International Cancer Research (AICR), Candis and Marie Curie Cancer Care, the Fondation de France, the Ligue Nationale Contre le Cancer, and l'Association pour la Recherche contre le Cancer.