Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression
Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression
复制标题
双特异性酪氨酸磷酸化调节激酶 3 丢失可激活嘌呤代谢并促进肝细胞癌进展。
DOI：
10.1002/hep.30703
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发表时间：
2019-11-01
期刊：
影响因子：
13.5
通讯作者：
Zhang, Zhiyong
中科院分区：
文献类型：
--
作者：
Ma, Fei;Zhu, Yuekun;Zhang, Zhiyong
癌细胞代谢不同的能量来源以快速产生生物质。嘌呤生物合成途径最近被确定为这些过程的代谢中间体的重要来源。然而，关于肝细胞癌（HCC）中嘌呤代谢的调控机制知之甚少。我们探讨了双特异性酪氨酸（Y）磷酸化调节激酶3（Dyrk 3）在HCC代谢中的作用。与正常对照组相比，HCC中Dyrk 3表达显著下调。其在HCC细胞中的引入显著抑制异种移植肿瘤模型中的肿瘤生长和转移。代谢产物的质谱分析表明，Dyrk 3对HCC的作用至少部分通过下调嘌呤代谢发生，如抑制嘌呤合成逆转了由Dyrk 3缺失介导的HCC进展的事实所证明的。我们进一步提供证据表明，Dyrk 3敲低的这种作用需要核受体共激活因子3（NCOA 3），NCOA 3已被证明是激活转录因子4（ATF 4）的共激活因子，以靶向嘌呤途径基因进行转录激活。从机制上讲，Dyrk 3直接磷酸化NCOA 3的Ser-1330，破坏其与ATF 4的结合，从而导致ATF 4转录活性的抑制。然而，磷酸化抗性NCOA 3-S1330 A突变体具有相反的效果。有趣的是，Dyrk 3的启动子活性受到ATF 4的负调控，表明存在双负反馈环。重要的是，Dyrk 3和磷酸化-NCOA 3-S1330的水平与人HCC标本中ATF 4的表达呈负相关。结论：我们的研究结果不仅阐明了Dyrk 3通过负调控NCOA 3/ATF 4转录因子复合物在重编程HCC代谢中的功能，而且还确定NCOA 3为Dyrk 3的磷酸化底物，表明Dyrk 3/NCOA 3/ATF 4轴作为HCC治疗的潜在候选者。
Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy.