UPP1 Promotes Lung Adenocarcinoma Progression through Epigenetic Regulation of Glycolysis

by Selleckchem | May 31 2023

Uridine phosphorylase 1 (UPP1) is a dimeric enzyme that plays an indispensable role in pyrimidine salvage as well as uridine homeostasis and is upregulated in various cancers, including LUAD. However, the function and underlying mechanisms of UPP1 in mediating LUAD cell progression are still largely unknown. Single-cell RNA transcription analysis was applied to compare the expression of UPP1 in tumor tissues and adjacent tissue. In vitro gain- and loss-of-function experiments with LUAD cells were performed to elucidate the functions of UPP1. Western blotting, qRT-PCR, cell apoptosis, IHC staining, Seahorse XF24 Extracellular Flux analysis, chromatin immunoprecipitation (ChIP) assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. In this study, UPP1 was found to be the top metabolism-related gene that was upregulated by single-cell transcriptomic profiling of LUAD. Next, we confirmed that UPP1 was highly expressed in LUAD tissues and cell lines and was correlated with poor overall survival in LUAD patients. UPP1 drove glycolytic metabolism and significantly regulated the sensitivity of tumors to glycolytic inhibitors in vitro and in vivo. UPP1 is subject to epigenetic regulation through histone acetylation. The CBP/p300 inhibitor SGC-CBP30 reduced the protein levels of UPP1, H3K27ac, and H3K9ac. ChIP assays revealed that acetyl-histone H3 and RNA polymerase II bind to the UPP1 promoter. UPP1 overexpression restored lactic acid production and glucose uptake compared to the SGC-CBP30 group. Our findings confirm UPP1 as a novel oncogene in LUAD, thus providing a potential novel diagnostic and therapeutic target for LUAD.

Comments：

The study described the characterization of the function and underlying mechanisms of Uridine phosphorylase 1 (UPP1) in mediating the progression of Lung Adenocarcinoma (LUAD) cells. The authors used single-cell RNA transcription analysis to compare the expression of UPP1 in tumor tissues and adjacent tissue and found UPP1 to be the top metabolism-related gene that was upregulated in LUAD. They further confirmed that UPP1 was highly expressed in LUAD tissues and cell lines and was correlated with poor overall survival in LUAD patients.

In vitro gain- and loss-of-function experiments with LUAD cells were performed to elucidate the functions of UPP1. The results showed that UPP1 drove glycolytic metabolism and significantly regulated the sensitivity of tumors to glycolytic inhibitors in vitro and in vivo. The study also found that UPP1 is subject to epigenetic regulation through histone acetylation. The CBP/p300 inhibitor SGC-CBP30 reduced the protein levels of UPP1, H3K27ac, and H3K9ac. ChIP assays revealed that acetyl-histone H3 and RNA polymerase II bind to the UPP1 promoter. UPP1 overexpression restored lactic acid production and glucose uptake compared to the SGC-CBP30 group.

The authors concluded that their findings confirm UPP1 as a novel oncogene in LUAD and provide a potential novel diagnostic and therapeutic target for LUAD. Overall, this study provides important insights into the molecular mechanisms underlying LUAD progression and identifies a potential target for the development of new therapeutic strategies.