Wang Ling, Zhang Qiang, Wang Jinping, Lu Hongzhao, Zeng Wenxian, Zhang Tao
School of Biological Science and Engineering, Shaanxi University of Technology, Dongguan Street South Campus, Hanzhong, 723001, Shaanxi Province, China.
College of Life Sciences, Key Laboratory of Plant Secondary Metabolism and Regulation of Zhejiang Province, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
Mol Divers. 2024 Oct;28(5):2863-2874. doi: 10.1007/s11030-023-10720-9. Epub 2023 Sep 9.
The activated form of vitamin D [1,25-dihydroxyvitamin D; 1,25(OH)D] 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)D and NSUN2 in melanoma cells remain largely unknown. The current study showed that 1,25(OH)D could significantly and specifically inhibit the proliferation and migration of melanoma B16 cells. 1,25(OH)D 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)D downregulated reporter gene expression was controlled by the Nsun2 promoter. The results suggest that 1,25(OH)D 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.
维生素D的活化形式[1,25 - 二羟基维生素D；1,25(OH)D]对多种生理过程至关重要，如骨矿化和钙代谢，并且在多种癌症中也发挥抗癌作用。其在黑色素瘤细胞中的作用尚未得到证实。NOP2 / Sun RNA甲基转移酶2（NSUN2）是一种典型的RNA甲基转移酶，在多种癌细胞中高表达。然而，1,25(OH)D和NSUN2在黑色素瘤细胞中作用的分子机制仍 largely未知。当前研究表明，1,25(OH)D可显著且特异性地抑制黑色素瘤B16细胞的增殖和迁移。1,25(OH)D增强维生素D受体表达，同时降低黑色素瘤细胞中NSUN2的表达。随后，敲低NSUN2可抑制B16细胞的增殖和迁移。RNA测序结果表明，敲低Nsun2后，DNA复制、细胞增殖和细胞周期途径富集，且促进这些途径的基因减少。双荧光素酶报告基因检测表明，1,25(OH)D下调报告基因表达受Nsun2启动子控制。结果表明，1,25(OH)D与位于Nsun2启动子上游的维生素D反应元件结合，下调Nsun2转录活性，进而影响与细胞增殖和细胞周期相关的基因表达模式，从而抑制B16细胞的增殖和迁移。
