Expression of DNA methyltransferase 1 is a hallmark of melanoma, correlates with response to BRAF and MEK inhibition and with proliferation in melanocytic tumors.

Aberrant DNA methylation is an epigenetic hallmark of melanoma and hypomethylating drugs with immunomodulatory activity are currently investigated in clinical trials. DNA methyltransferase 1 (DNMT1) is the major maintenance methyltransferase but its expression in melanocytic tumors is unknown. We analyzed DNMT1 expression in primary melanocytes, melanoma cell lines and 83 melanocytic tumors and explored its association with proliferation, mutational status and response to BRAF and MEK inhibition. We found that DNMT1 expression increased incrementally from nevi (mean fluorescence intensity (MFI) 48.1, interquartile range (IQR) 41.7 - 59.6) to primary melanomas (MFI 68.8, IQR 58.4 - 77.0) and metastatic melanomas (MFI 87.5, IQR 77.1 - 114.5; P < 0.001). DNMT1 expression correlated with Ki67 expression (Spearman correlation 0.483; P < 0.001) and was independent of the BRAF mutational status (P = 0.55). In BRAF mutant melanoma, DNMT1 was downregulated during response to BRAF and MEK inhibition and was again upregulated upon drug resistance in vitro and in vivo. Degradation of DNMT1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid decreased cell viability in BRAF inhibitor sensitive and resistant cell lines. Our study demonstrates that DNMT1 expression correlates with proliferation in melanocytic tumors, increases with melanoma progression and is associated with response to BRAF and MEK inhibition. Given its strong expression in metastatic melanoma, DNMT1 may be a promising target for combined epigenetic and immunotherapy.