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.

中文翻译：

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UHMK1 通过重编程核苷酸代谢促进胃癌进展。


UHMK1 是一种核丝氨酸/苏氨酸激酶，最近与癌发生有关。然而，UHMK1在人胃癌（GC）发病机制中的功能和作用机制尚不清楚。在这里，我们观察到 UHMK1 在 GC 中显着上调。 UHMK1 沉默强烈抑制 GC 攻击性。有趣的是，UHMK1 诱导的 GC 进展主要是通过增强嘌呤从头合成来介导的，因为抑制嘌呤合成可以逆转 UHMK1 过表达的影响。从机制上讲，UHMK1通过磷酸化NCOA3的Ser（S）1062和Thr（T）1067位点来激活ATF4（核苷酸合成中的重要转录因子）。该事件显着增强了NCOA3与ATF4的结合以及嘌呤代谢相关靶基因的表达。相反，NCOA3 在 S1062/T1067 处的磷酸化缺陷显着消除了 UHMK1 在 GC 发育中的功能。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 GC 标本中 UHMK1 的水平与磷酸-NCOA3 (S1062/T1067) 的水平显着相关。总的来说，这些结果表明 UHMK1 激活的嘌呤从头合成途径显着促进 GC 的发展。