Abstract
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, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect 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. Alternative inhibitors of c-MET showed similar results. 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.
Highlights
The incidence of melanoma has increased markedly over the past three decades[1]
BRN2 expression reduces cell proliferation To investigate the role of BRN2 in melanoma progression and metastasis, we initially screened a panel of cell lines and determined the constitutive expression of BRN2 (Supplementary Fig. S1)
We sequentially stably transduced melanoma cell lines, including two lines with low levels of BRN2, with lentivirus expressing the tetracycline (Tet) repressor followed by BRN2 or lacZ, as a negative control, under the control of the CMV/TetO2 promoter leading to high levels of BRN2 expression (Supplementary Fig. S2)
Summary
The incidence of melanoma has increased markedly over the past three decades[1]. It is estimated that ~288,000 people will be diagnosed with malignant melanoma worldwide in 2019, with over 60,000 dying from the disease[2]. The 5-year survival of patients following surgical removal of thin primary tumors (
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