The dark side of the light (UVA): melanoma microenvironment and cell survival strategies

Abstract The incidence of cutaneous melanoma is rapidly escalating in many developed countries, particularly among the aging populations. Extensive evidence shows epigenetic changes have a strong correlation between cutaneous malignant melanoma and exposure to sunlight, particularly its ultraviolet (UV) components, in the aging skin. While significant research has been conducted on aging and its associated S enescence- A ssociated S ecretory P henotype (SASP) contributed by senescent fibroblasts in old individuals, less is known about the role of UVA radiation in such SASP melanoma microenvironment, its effects on gene function, and the underlying mechanisms following U VA-induced D NA D amage (UDD). It is established that UVA radiation induces D ouble- S trand B reaks (DSBs) in DNA and activates checkpoint kinase 2 (Chk2) at these breaks, leading to p53-mediated apoptosis. But p53, beyond its role in regulating cell fate, its mutated form is also involved in the transcriptional regulation of potent pro-survival pathways by actively transcribing genes that counteract apoptosis in genetically abnormal melanoma cells. However, the molecular mechanisms that govern the fine balance between cell death and survival mediated by the p53 transcription factor under UVA exposure remain largely elusive. In this study, we report for the first time that UVA induces global DNA methylation as a compensatory mechanism in response to U VA-induced D NA D amage (UDD) in melanoma and melanocyte cells. However, melanoma cells in the vicinity of senescent fibroblasts under genotoxic stress are epigenetically altered by the paracrine secretion of interleukin-6 (IL-6) from senescent fibroblasts, which upregulates the anti-apoptotic gene GDF-15 as well as the DNA damage repair system. This upregulation occurs via hypomethylation of GDF-15 orphan CpG island promoters, followed by its active gene transcription of GDF-15 via both WT p53 Ser392 and Mutated p53 N239Y transcription factors, thereby enhancing pro-survival mechanisms that contribute to melanoma progression.