Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming.

Abstract

Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target.

• Authors: Jia Liu, Ze-Xian Liu, Qi-Nian Wu, Yun-Xin Lu, Chau-Wei Wong, Lei Miao, Yun Wang, Zixian Wang, Ying Jin, Ming-Ming He, Chao Ren, De-Shen Wang, Dong-Liang Chen, Heng-Ying Pu, Lin Feng, Bo Li, Dan Xie, Mu-Sheng Zeng, Peng Huang, Aifu Lin, Dongxin Lin, Rui-Hua Xu, Huai-Qiang Ju
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 1507 (03 20 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32198345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Long Noncoding
• PFKFB3 protein, human
• Phosphofructokinase-2

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cellular Reprogramming (physiology)
• Esophageal Squamous Cell Carcinoma (metabolism)
• Female
• Gene Knockout Techniques
• Glycolysis
• Humans
• Mice, Inbred BALB C
• Mice, Nude
• Phosphofructokinase-2 (metabolism)
• Pseudogenes (genetics, physiology)
• RNA, Long Noncoding (genetics, metabolism)
• Up-Regulation
• Xenograft Model Antitumor Assays