UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism
UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism
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UHMK1通过重编程核苷酸代谢促进胃癌进展
DOI：
10.15252/embj.2019102541
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发表时间：
2020-01-23
期刊：
影响因子：
11.4
通讯作者：
Zhang, Zhiyong
中科院分区：
文献类型：
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作者：
Feng, Xing;Ma, Dong;Zhang, Zhiyong
UHMK1是最近参与肿瘤发生的一种核丝氨酸/苏氨酸激酶。然而，UHMK1在人胃癌发病机制中的作用和作用机制尚不清楚。在这里，我们观察到UHMK1在GC中明显上调。UHMK1沉默强烈地抑制了GC的侵袭性。有趣的是，UHMK1诱导的GC进展主要是通过促进从头合成嘌呤来介导的，因为抑制嘌呤合成逆转了UHMK1过表达的影响。机制上，UHMK1通过磷酸化Ser(S)1062和Thr(T)1067上的NCOA3，激活核苷酸合成中的一个重要转录因子ATF4。这一事件显著增强了NCOA3与ATF4的结合和嘌呤代谢相关靶基因的表达。相反，S1062/T1067上NCOA3的磷酸化缺陷显著降低了UHMK1在GC发育中的作用。在临床上，幽门螺杆菌和GC相关的UHMK1突变诱导NCOA3-S1062/T1067磷酸化，并增强ATF4和UHMK1的活性。重要的是，人胃癌标本中UHMK1的水平与磷酸化NCOA3(S1062/T1067)的水平显著相关。总之，这些结果表明，UHMK1激活的从头合成嘌呤途径显著促进了GC的发展。
UHMK1 is a nuclear serine/threonine kinase recently implicated in carcinogenesis. However, the functions and action mechanisms of UHMK1 in the pathogenesis of human gastric cancer (GC) are unclear. Here, we observed that UHMK1 was markedly upregulated in GC. UHMK1 silencing strongly inhibited GC aggressiveness. Interestingly, UHMK1-induced GC progression was mediated primarily via enhancing de novo purine synthesis because inhibiting purine synthesis reversed the effects of UHMK1 overexpression. Mechanistically, UHMK1 activated ATF4, an important transcription factor in nucleotide synthesis, by phosphorylating NCOA3 at Ser (S) 1062 and Thr (T) 1067. This event significantly enhanced the binding of NCOA3 to ATF4 and the expression of purine metabolism-associated target genes. Conversely, deficient phosphorylation of NCOA3 at S1062/T1067 significantly abrogated the function of UHMK1 in GC development. Clinically, Helicobacter pylori and GC-associated UHMK1 mutation induced NCOA3-S1062/T1067 phosphorylation and enhanced the activity of ATF4 and UHMK1. Importantly, the level of UHMK1 was significantly correlated with the level of phospho-NCOA3 (S1062/T1067) in human GC specimens. Collectively, these results show that the UHMK1-activated de novo purine synthesis pathway significantly promotes GC development.