BRN2 expression increases anoikis resistance in melanoma.

Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, how BRN2 functions during the metastatic process of melanoma remains largely unknown. We therefore investigated the effects of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2 expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2 expressing cells under non-adherent conditions to death by anoikis. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2 expressing cells resistant to therapy and cell death by anoikis. melanoma cells, expressing BRN2 or vector, were treated with 50 ng/ml doxycycline for either 24 or 48 hours; Single colour, Illumina Human HT12v4 Beadarrays.