Expression of proteins involved in epigenetic regulation in human cutaneous melanoma and peritumoral skin

Abstract

Epigenetic processes play a critical role in melanoma development. However, little is known about proteins responsible for epigenetic transformations in melanoma cells. The processes in the peritumoral skin within the excision margin are almost unstudied. We studied the changes in expression of 112 proteins involved in epigenetic regulation of gene expression in the human cutaneous melanoma and its peritumoral zone using "The Proteomic Antibody Microarrays" (GRAA2, Sigma-Aldrich). Dimethylated histone H3 at lysines 4 and 9 as well as proteins involved in the regulation of transcription (histone deacetylases HDAC-1 and HDAC-11, DNA methyl-binding protein Kaiso), cell cycle control (protein kinases Aurora-В and PKR, chromosome protein CENP-E , and phosphorylated and acetylated histone H3), DNA repair (phosphorylated histone H2AX), and nuclear protein import (importins α3 and α5/7) were over-expressed in the melanoma tissue as compared with normal skin. At the same time, HDAC-10 and proliferating cell nuclear antigen PCNA were downregulated. In the peritumoral skin, at the excision margin (1-2 cm from the melanoma edge), we observed similar changes in expression of these proteins and, additionally, over-expression of arginine methyltransferases PRMT5 and NAD-dependent histone deacetylase SIR2. Histone methyltransferase G9a and metastasis-associated protein 2 were downregulated. Therefore, epigenetic regulation that requires histone modifications and expression of some regulatory proteins is of importance for melanoma development and propagation. The observed changes in the peritumoral skin may indicate the epigenetic pre-tuning in this zone possibly involved in malignant transformation. These results can be potentially useful for melanoma diagnostics and targeted therapy.

Uveal melanoma: progress in molecular biology and therapeutics

“…The overall levels of H3K9me2 in melanoma tissues are higher than those in normal skin, which is mainly regulated by euchromatic histone lysine N-methyltransferase 2 (EHMT2/G9A). 119 , 120 In several cancer subtypes, inhibition of EHMT2 led to the arrest of tumor growth. 121 …”

Tackling malignant melanoma epigenetically: histone lysine methylation

“…H3K4me2 is also an active histone mark enriched in sites toward the 5′-end of transcribing genes and present in several melanoma cell lines. An increase in the level of H3K4me2 has been observed in melanoma samples compared to normal skin of the same patients [ 62 ]. Interestingly, H3K4me2 levels were found to be lower in metastatic melanoma compared to primary tumors [ 63 ].…”

“…EHMT . Dimethylated H3K9 has a higher global level in melanoma samples compared to the normal skin tissue [ 62 ]. EHMT2 (G9A) mono- and dimethylates H3K9.…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…DOT1L plays an important protective role in ultraviolet radiation-induced melanomagenesis [ 65 ]. H3K9me2 levels were also found to be increased in melanoma compared to normal skin tissue [ 66 ] whereas H3K27me3 levels were lower in metastatic versus primary melanoma cases [ 67 ]. In parallel, low H3K18ac levels in cancer were already correlated with poor patient outcomes [ 68 ] and the decrease in H3K23me1 was also verified in breast cancer when compared to normal tissues [ 69 ].…”