LAUSR

Histone modifications play a significant role in the development and progression of various cancers. The histone methyltransferase SETDB1 (SET domain, bifurcated 1) catalyzes the addition of methyl groups to histone H3 at lysine 9 (H3K9). In the present study, we demonstrate that SETDB1 contributes to melanoma tumorigenesis. We show SETDB1 to be highly amplified in melanoma tissues of patients with poor prognosis. The amplification of SETDB1 correlates with the increased expression of the protein. Functional studies show an increased SETDB1 expression to be associated with a more proliferative, invasive and migratory phenotype and give rise to larger tumor masses in xenograft mouse models. In human primary melanomas, SETDB1 expression is elevated at the invasive borders. The activity of SETDB1 can be blocked by small molecules, which leads to reduced cell growth even in melanoma cell lines that are resistant towards BRAF and MEK inhibitors. In conclusion, our findings support SETDB1 as a major driver of melanoma development and progression. We therefore suggest SETB1 as a potential future target for the treatment of melanoma. Citation Format: Elias Orouji, Aniello Federico, Lionel Larribere, Daniel Novak, Jochen Utikal. The histone methyltransferase SETDB1 contributes to melanoma tumorigenesis [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A180.