The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma
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DOI：
10.1016/j.celrep.2019.05.069
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发表时间：
2019-06-18
期刊：
影响因子：
8.8
通讯作者：
Jonsson, Goran
中科院分区：
文献类型：
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作者：
Phung, Bengt;Ciesla, Maciej;Jonsson, Goran
X连锁DDX3X基因编码ATP依赖性DEAD盒RNA解旋酶，在包括黑色素瘤在内的各种人类癌症中经常发生改变。尽管DDX3X在翻译和剪接中发挥重要作用，但其功能障碍如何特异性地重新连接黑色素瘤中的基因表达仍然完全未知。在这里，我们发现了一个DDX3X驱动的转录后程序，决定了黑色素瘤表型和疾病预后不良。通过对翻译核糖体的无偏分析，我们确定了小眼症相关转录因子MITF是一个关键的DDX3X翻译靶点，它指导黑色素瘤细胞的增殖转移表型转换。在机制上，DDX3X通过嵌入在5' UTR内的内部核糖体进入位点（IRES）控制MITF mRNA翻译。通过这种精致的基于抑制的调节机制，DDX3X控制MITF蛋白水平，决定体内黑色素瘤转移潜力和对靶向治疗的反应。总之，这些发现揭示了基因调控的转录后层，这可能为侵袭性男性黑色素瘤提供独特的治疗漏洞。
The X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5' UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.