UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism

• Published in: The EMBO journal 2020-03, Vol.39 (5), p.e102541-n/a
• Main Authors: Feng, Xing, Ma, Dong, Zhao, Jiabao, Song, Yongxi, Zhu, Yuekun, Zhou, Qingxin, Ma, Fei, Liu, Xing, Zhong, Mengya, Liu, Yu, Xiong, Yubo, Qiu, Xingfeng, Zhang, Zhen, Zhang, Heng, Zhao, Yongxiang, Zhang, Kaiguang, Hong, Xuehui, Zhang, Zhiyong
• Format: Article
• Language: English
• Subjects: Animals; ATF4; Binding; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Disease Progression; EMBO03; EMBO21; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Helicobacter pylori; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Male; Metabolism; Mice; Mice, Inbred BALB C; Mutation; NCOA3; Nuclear Receptor Coactivator 3 - genetics; Nuclear Receptor Coactivator 3 - metabolism; Nucleotides; Nucleotides - metabolism; Pathogenesis; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-serine/threonine kinase; purine metabolism; Stomach - pathology; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Synthesis; UHMK1; Up-Regulation
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2019102541

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. Synopsis This study delineates a new role for the nuclear serine/threonine kinase UHMK1 as driver of gastric cancer (GC) via regulating purine metabolism and NCOA3/ATF4‐mediated gene expression control. Levels of UHMK1 and NCOA3 phosphorylation are promising stratifiers for patient outcome. UHMK1 expression is significantly upregulated in GC and correlates with poor clinical outcome. UHMK1 directly phosphorylates NCOA3 at Ser1062 and Thr1067 residues. NCOA3‐S1062/T1067 phosphorylation promotes ATF4 binding, expression of purine metabolic target genes, and GC progression. Helicobacter pylori infection and GC‐related UHMK1 mutation (M134T and T217K) enhance NCOA3‐S1062/T1067 phosphorylation, activity of ATF4 and UHMK1. Graphical Abstract Nuclear serine/threonine kinase UHMK1 mutations enhance gastric cancer by activating de novo purine synthesis.