IDDF2022-ABS-0083 Epigenetic induction of mitochondrial proline synthase PYCR1 promotes gastric cancer progression by regulating mitochondrial dynamics and purine metabolism

Abstract

<h3>Background</h3> Reprogramming of amino acid metabolism is critical for tumor growth. We have reported that upregulation of pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme in mitochondrial proline anabolism, contributes to gastric cancer (GC) progression and indicates poor survival. However, the PYCR1 expression profile in GC subtypes and the underlying mechanisms behind its upregulation, as well as the promotion of GC progression are not well-studied. <h3>Methods</h3> PYCR1 expression profiles in GC subtypes and stages of gastric carcinogenesis were assessed in different cohorts. Genetic alterations and epigenetic modulation in PYCR1 regulation were investigated in tumor tissues and GC cell lines. The effect of PYCR1 on GC progression was further investigated from the perspectives of mitochondrial function and intracellular metabolism. <h3>Results</h3> PYCR1 expression was significantly higher in intestinal-type GC and associated molecular subtypes in two independent GC cohorts. During the Correa cascade of gastric carcinogenesis, PYCR1 was continuously increased from normal gastric tissues to atrophic gastritis with or without intestinal metaplasia, through to dysplasia, and finally to cancerous lesions. Hypomethylation and p300-mediated H3K27ac acetylation activation in <i>PYCR1</i> promotor synergistically facilitated PYCR1 transcription. PYCR1 depletion or overexpression attenuated or promoted GC cell proliferation, but did not have any effect on the cell cycle. PYCR1 inhibition decreased mitochondrial DNA copy number in GC cells, but had no effect on mitochondrial membrane potential, mitochondrial mass and oxidative stress response. Detection of intracellular metabolite profiles revealed that PYCR1 depletion had a significant effect on intracellular purine metabolism (hypoxanthine, inosine and adenosine monophosphate), which was associated with cell growth inhibition. Furthermore, depletion of PYCR1 restored mitochondrial networking via enhancing mitochondrial fusion, leading to inhibition of cell proliferation. Consistently, pharmacological enhancement with Mdivi-1 of mitochondrial fusion also brought about the similar effects. Conversely, PYCR1 overexpression promoted mitochondrial fission, contributing to tumor growth. <h3>Conclusions</h3> PYCR1 overexpression was heterogeneous in different GC subtypes, and an increase in PYCR1 was an early event in the multistep of gastric carcinogenesis. Epigenetic modulation synergistically contributes to PYCR1 upregulation in GC, resulting in tumor progression via enhancing mitochondrial fission and coupling with purine metabolic reprogramming. Collectively, PYCR1 might be a promising therapeutic target for GC.