Vitamin D3 regulates NSUN2 expression and inhibits melanoma cell proliferation and migration

The activated form of vitamin D₃ [1,25-dihydroxyvitamin D₃; 1,25(OH)₂D₃] is important for various physiological processes, such as bone mineralization and calcium metabolism, and plays an anticancer role in numerous cancers as well. Its role in melanoma cells has yet to be proven. NOP2/Sun RNA methyltransferase 2 (NSUN2) is a typical RNA methyltransferase and is highly expressed in a variety of cancer cells. However, the molecular mechanisms underlying the role of 1,25(OH)₂D₃ and NSUN2 in melanoma cells remain largely unknown. The current study showed that 1,25(OH)₂D₃ could significantly and specifically inhibit the proliferation and migration of melanoma B16 cells. 1,25(OH)₂D₃ enhances vitamin D receptor expression while simultaneously reducing NSUN2 expression in melanoma cells. Subsequently, knockdown of NSUN2 suppressed B16 cell proliferation and migration. RNA-Seq results illuminated that DNA replication, cell proliferation and cell cycle pathways were enriched, and genes promoting these pathways were reduced after knocking down Nsun2. Dual-luciferase reporter assays showed that 1,25(OH)₂D₃ downregulated reporter gene expression was controlled by the Nsun2 promoter. The results suggest that 1,25(OH)₂D₃ binds to the vitamin D response element located upstream of the Nsun2 promoter to downregulate Nsun2 transcription activity and then affects the gene expression pattern related to cell proliferation and the cell cycle, thereby restraining B16 cell proliferation and migration.