UHMK 1 promotes gastric cancer progression through reprogramming nucleotide metabolism

Abstract

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 progressionwas mediated primarily via enhancing de novo purine synthesis because inhibiting purine synthesis reversed the effects of UHMK1 overexpression. Mechanistically, UHMK1 acti- vated 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 expres- sion of purine metabolism-associated target genes. Conversely, defi- cient phosphorylation of NCOA3 at S1062/T1067 significantly abrogated the function of UHMK1 in GC development. Clinically, Heli- cobacter pylori and GC-associated UHMK1 mutation induced NCOA3- S1062/T1067 phosphorylation and enhanced the activity of ATF4 and UHMK1.Importantly,the level ofUHMK1 was significantly correlated with the level of phospho-NCOA3 (S1062/T1067) in human GC speci- mens. Collectively, these results show that the UHMK1-activated de novo purine synthesis pathway significantly promotes GC development.