As
melanoma cells are immunogenic, they instigate an adaptive immune response and production of anti-
tumor T-cells. A central factor in this interaction is
CEACAM1 (
carcinoembryonic antigen cell adhesion molecule 1), a transmembrane
glycoprotein previously shown in our lab to protect
melanoma cells from T cell-mediated killing. In this study, we examine the role of
transcription factor SOX9 in the regulation of
CEACAM1 expression and immune resistance in
melanoma cells. Knockdown of endogenous SOX9 results in
CEACAM1 up-regulation, while its overexpression leads to the opposite effect. We show that SOX9 controls
CEACAM1 expression at a transcriptional level, but in an indirect manner, as regulation of the
CEACAM1 promoter remains intact even when all eight potential SOX9-binding sites are abolished. A series of promoter truncations localizes the SOX9-controlled area to the proximal 200bp of the promoter. Point mutations in putative Sp1 and ETS1 binding sites identify these
transcription factors as the primary SOX9-controlled mediators. Co-immunoprecipitation studies show that SOX9 and Sp1 physically interact in
melanoma cells, while silencing of SOX9 down-regulates ETS1, but not Sp1, in the same cells. Finally, knockdown of SOX9 indeed renders
melanoma cells resistant to T cell-mediated killing, in line with the increased
CEACAM1 expression. In conclusion, we show that SOX9 regulates
CEACAM1 expression in
melanoma cells, and thereby their immune resistance. As
CEACAM1 is a pivotal
protein in
melanoma biology and immune crosstalk, further understanding of its regulation can provide new insights and contribute to the development of novel approaches to
therapy.