THE BRN-2 GENE REGULATES THE MELANOCYTIC PHENOTYPE AND TUMORIGENIC POTENTIAL OF HUMAN-MELANOMA CELLS

The Oct transcription factors N-Oct-3 and N-Oct-5 are differentially e xpressed in normal melanocytes, melanoma tumors and cell lines. We hav e cloned the human brn-2 gene and have shown that it encodes both the N-Oct-3 and N-Oct-5 octamer binding activities detected in melanoma ce lls. The brn-2 genomic locus has been mapped to chromosome 6q16 and al though chromosomal aberrations are common in this region in melanoma, no deletion or rearrangement of the brn-2 gene in melanoma cell lines was observed. Sequencing of the entire gene showed that there are no i ntervening sequences within the open reading frame. Antisense RNA-medi ated inhibition of brn-2 gene expression in melanoma cells was associa ted with a change in morphology and loss of melanocytic and neural cre st markers, including the melanocyte transcription factor microphthalm ia and the TYRP pigmentation genes. In addition, loss of brn-2 in thes e cells resulted in the complete loss of ability to form tumors in SCI D and nu/nu mice. These results suggest roles for brn-2 in the determi nation of the melanocytic lineage and in the tumorigenic phenotype of melanoma.