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 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.

Urine metabolomics of rats with chronic atrophic gastritis

“…Purine metabolism provides cells with the necessary energy and cofactors to promote the growth and proliferation of cells. The most common disease with purine dysfunction is gout, and purine metabolism and its metabolites include adenosine monophosphate, adenosine, adenine, and, at times, the abnormal expression of xanthine, guanosine and guanine will promote the occurrence of gastric cancer [ 24 ]. The decomposition of purine nucleotides will promote the dephosphorylation of inosine or guanylic acid and generate inosine or guanosine, which can decompose into xanthine or guanine.…”

Urine metabolomics of rats with chronic atrophic gastritis

“…Ammonia can simulate toxic damage to the stomach after Purine metabolism provides cells with the necessary energy and cofactors to promote the growth and proliferation of cells. The most common disease with purine dysfunction is gout, and purine metabolism and its metabolites include adenosine monophosphate, adenosine, adenine, and, at times, the abnormal expression of xanthine, guanosine and guanine will promote the occurrence of gastric cancer [24]. The decomposition of purine nucleotides will promote the dephosphorylation of inosine or guanylic acid and generate inosine or guanosine, which can decompose into xanthine or guanine.…”

Emerging roles of nucleotide metabolism in cancer development: progress and prospect

“…Hong et al found that the nucleotide metabolism of digestive tract tumor cells varies in different diseased organs of the digestive tract, showing obvious organ specificity. By conducted more in-depth research using digestive tract tumors from different pathogenic organs as models, a specific key kinase that regulates the rate-limiting enzyme activity of nucleotide metabolism was discovered; in research on nucleotide synthesis and metabolism in gastric cancer, the kinase UHMK1 involved in the nucleotide anabolism of gastric cancer was found to activate the de novo rate-limiting purine anabolism-related enzymes 5′-aminoimidazole-4′-carboxamide ribonucleotide formyltransferase (ATIC) and inosine monophosphate dehydrogenase (IMPDH) by regulating the NCOA3/ATF4 axis, promoting the occurrence and development of gastric cancer [ 62 ]. In research on nucleotide anabolism in cholangiocarcinoma, CDC like kinase 3 (CLK3) was found to activate the rate-limiting enzyme in de novo purine anabolism, ATIC, by regulating the USP13/Fbxl14/c-Myc signaling axis, thereby promoting the molecular progression of cholangiocarcinoma.…”