Codon-specific translation reprogramming promotes resistance to targeted therapy
Codon-specific translation reprogramming promotes resistance to targeted therapy
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DOI：
10.1038/s41586-018-0243-7
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发表时间：
2018-06-28
期刊：
影响因子：
64.8
通讯作者：
Close, Pierre
中科院分区：
文献类型：
--
作者：
Rapino, Francesca;Delaunay, Sylvain;Close, Pierre
信使核糖核酸翻译的重新编程在癌症的发展和耐药性中起着关键作用(1)。然而，参与这一过程的分子机制仍然知之甚少。在翻译过程中，特定密码子的解码需要摆动tRNA修饰(2，3)。在人类中，我们表明，催化摆动尿苷34(U-34)tRNA(U-34酶)修饰的酶是蛋白质合成重排的关键角色，这是由BRAF(V600E)癌基因驱动的转化和黑色素瘤靶向治疗耐药所诱导的。我们发现表达BRAF(V600E)的黑色素瘤细胞依赖U34酶生存，同时抑制MAPK信号与ELP3或CTU1和/或CTU2协同作用杀死黑色素瘤细胞。PI3K信号通路的激活是MAPK治疗药物获得性耐药的最常见机制之一，它显著增加了U-34酶的表达。在机制上，U-34酶通过直接调节HIF1a mRNA的翻译和维持高水平的HIF1α蛋白来促进黑色素瘤细胞的糖酵解。因此，对抗BRAF治疗的获得性抵抗与高水平的U-34酶和HIF1α有关。综上所述，这些结果表明U-34酶通过调节特定的mRNA翻译来促进黑色素瘤细胞的存活和对治疗的抵抗力。
Reprogramming of mRNA translation has a key role in cancer development and drug resistance(1). However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation(2,3). Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U-34) tRNA (U-34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF(V600E) oncogene and by resistance to targeted therapy in melanoma. We show that BRAF(V600E)-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U-34 enzymes. Mechanistically, U-34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1 alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U-34 enzymes and HIF1 alpha. Together, these results demonstrate that U-34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.