The histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target in BRAF/MEK inhibitor-resistant melanoma [ChIP-seq]

Histone modifications play a crucial role in the progression of various cancers. The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9. Here, we describe SETDB1 contribution to melanoma tumorigenesis. SETDB1 is highly amplified in melanoma cells and in patients' tumors. Increased SETDB1 expression, which correlates with SETDB1 amplification, is associated with a more aggressive phenotype in in vitro and in vivo studies. SETDB1 implements its effects through the regulation of Thrombospondin 1. SETDB1's SET-domain is essential to maintain its tumorigenic effects. SETDB1 inhibition reduces cell growth in melanomas resistant to targeted treatments. In essence, we support SETDB1 as a major driver of melanoma development, highlighting a role as potential future target for the treatment of this disease. Overall design: Chromatin obtained from SETDB1-OE (C32) and -knockdown (SK-HI-SETDB1) melanoma cell lines, together with the corresponding control cells, was immunoprecipitated with anti-H3K9me3 and anti-H3K4me1 antibodies. Next, chromatin-immunoprecipitated DNA libraries were prepared and sequenced.