Abstract
The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
Highlights
Melanoma ranks among the deadliest types of skin cancer and accounts for the vast majority of deaths from cutaneous neoplasms
We investigated epigenetic mechanisms that are involved in the regulation of the BRN3A expression in melanocytes and melanoma cells
We propose an annotated enhancer region of BRN3A that was hyperacetylated after inhibition of histone deacetylase 2 (HDAC2)
Summary
Melanoma ranks among the deadliest types of skin cancer and accounts for the vast majority of deaths from cutaneous neoplasms. Its inhibition leads to an arrest in the G1 phase of the cell cycle mediated by p53 and subsequent apoptosis via the intrinsic apoptosis pathway in BRN3A high-expressing melanoma cells but not in melanocytes This was evident due to the cleavage of caspase 3 and 9 but not of caspase 8. HDAC1, HDAC2, HDAC3, and HDAC8 belong to the best-studied class I HDACs and are involved in the modulation of gene expression, cell cycle progression, and DNA damage control [21]. Their involvement in the regulation of melanoma oncogenes is little established. We propose an annotated enhancer region of BRN3A that was hyperacetylated after inhibition of HDAC2
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