Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Int J Mol Sci. 2019 Jan 29;20(3):576. doi: 10.3390/ijms20030576.
Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop between Notch signaling and microphthalmia-associated transcription factor (MITF), the central regulator of melanoma progression and the driver of melanoma plasticity. We further demonstrate that Notch signaling activation, in addition to the known competition-based repression mechanism of MITF transcriptional activity, inhibits the transcription of MITF, leading to a decrease in MITF expression. We also found that MITF binds to the promoter of the gene encoding the master regulator of Notch signaling, recombination signal binding protein J kappa (RBPJK), leading to its upregulation. Our findings suggest that, once activated, Notch signaling represses MITF signaling to maintain the melanoma invasiveness and metastatic phenotype.
黑色素瘤是一种源于黑色素细胞的肿瘤，是一种高度转移性和治疗抵抗性癌症。虽然 Notch 信号通路的激活促进黑色素瘤的进展已得到充分证实，但 Notch 信号通路与黑色素瘤特异性通路之间的相互作用却知之甚少。在这里，我们揭示了 Notch 信号通路与小眼畸形相关转录因子（MITF）之间的负反馈调节环，MITF 是黑色素瘤进展的核心调节因子，也是黑色素瘤可塑性的驱动因子。我们进一步证明，Notch 信号通路的激活，除了已知的基于竞争的 MITF 转录活性抑制机制外，还抑制了 MITF 的转录，导致 MITF 表达减少。我们还发现 MITF 结合到编码 Notch 信号通路主要调节因子重组信号结合蛋白 J kappha（RBPJK）的基因的启动子上，导致其上调。我们的研究结果表明，一旦 Notch 信号通路被激活，它就会抑制 MITF 信号通路，以维持黑色素瘤的侵袭性和转移性表型。
