IDDF2018-ABS-0184 LNCRNA AGPG regulates anabolism remodelling through affecting PFKFB3 stability in escc

Background Tumour cells often exhibit altered energy metabolism for tumour progression, but whether long noncoding RNAs (lncRNAs) are involved in this process remains elusive. We aimed to identify novel lncRNAs significantly affecting the development of Esophageal Squamous Cell Carcinoma (ESCC) and investigate the metabolism-related mechanisms. Methods A siRNA library was established using top 100 lncRNAs highly expressed in ESCC screened from TCGA database and transfected into ESCC cells to identify lncRNAs that significantly affected cell glucose metabolism and proliferation. RNAscope in situ hybridization, qRT-PCR and RNAi assays were performed to investigate the functional role of lncRNA AGPG ( A ctin G amma 1 P seudo g ene) and clinical relevance. In vivo , cell-based and patient-derived xenograft (PDX) models were used to further explore roles of AGPG in ESCC tumorigenesis. RNA pull-down, mass spectrometry analyses, western blot and RNA-binding protein immunoprecipitation (RIP) were performed to identify interaction proteins and related mechanisms. Results We identified that lncRNA AGPG was markedly increased in ESCC and correlated with poor prognosis. AGPG depletion significantly repressed ESCC cell proliferation and glycolytic activity including decreased glucose uptake and increased lactate production. In vivo experiments further showed that silencing AGPG decreased tumours growth in cell-based xenografts and PDX models. Mechanistically, AGPG could interact with 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) in the nucleus, thus enhancing PFKFB3 stability via preventing its ubiquitination and proteosomal degradation. Subsequently, AGPG-PFKFB3 promoted glycolysis and dysregulated cell cycle by suppressing p27 and over-activating cyclin-dependent kinase 1(CDK1), thereby leading to G1/S cell cycle progression. Additionally, TP53 could bind to the promoter of AGPG to negatively regulate its expression. Conclusions We first identified that AGPG , which is regulated by TP53 , is playing a pivotal role in glucose metabolism remodelling and cell proliferation through enhancing PFKFB3 stability, thus facilitating the development of ESCC. Collectively, our study suggests that TP53-AGPG -PFKFB3 axis might serve as potential biomarkers and therapeutic targets in ESCC.