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UHMK 1 promotes gastric cancer progression through reprogramming nucleotide metabolism
Author(s) -
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
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102541
Subject(s) - china , beijing , medicine , general hospital , family medicine , library science , general surgery , history , archaeology , computer science
UHMK 1 is a nuclear serine/threonine kinase recently implicated in carcinogenesis. However, the functions and action mechanisms of UHMK 1 in the pathogenesis of human gastric cancer ( GC ) are unclear. Here, we observed that UHMK 1 was markedly upregulated in GC . UHMK 1 silencing strongly inhibited GC aggressiveness. Interestingly, UHMK 1‐induced GC progression was mediated primarily via enhancing de novo purine synthesis because inhibiting purine synthesis reversed the effects of UHMK 1 overexpression. Mechanistically, UHMK 1 activated ATF 4, an important transcription factor in nucleotide synthesis, by phosphorylating NCOA 3 at Ser (S) 1062 and Thr (T) 1067. This event significantly enhanced the binding of NCOA 3 to ATF 4 and the expression of purine metabolism‐associated target genes. Conversely, deficient phosphorylation of NCOA 3 at S1062/T1067 significantly abrogated the function of UHMK 1 in GC development. Clinically, Helicobacter pylori and GC ‐associated UHMK 1 mutation induced NCOA 3‐S1062/T1067 phosphorylation and enhanced the activity of ATF 4 and UHMK 1. Importantly, the level of UHMK 1 was significantly correlated with the level of phospho‐ NCOA 3 (S1062/T1067) in human GC specimens. Collectively, these results show that the UHMK 1‐activated de novo purine synthesis pathway significantly promotes GC development.