Lipid metabolism–related lncRNA SLC25A21‐AS1 promotes the progression of oesophageal squamous cell carcinoma by regulating the NPM1/c‐Myc axis and SLC25A21 expression

Abstract

Background Obesity alters metabolic microenvironment and is thus associated with several tumours. The aim of the present study was to investigate the role, molecular mechanism of action, and potential clinical value of lipid metabolism–related long non‐coding RNA (lncRNA) SLC25A21‐AS1 in oesophageal squamous cell carcinoma (ESCC). Methods A high‐fat diets (HFDs)‐induced obesity nude mouse model was established, and targeted metabolomics analysis was used to identify critical medium‐long chain fatty acids influencing the growth of ESCC cells. Transcriptomic analysis of public dataset GSE53625 confirmed that lncRNA SLC25A21‐AS1 was a lipid metabolism–related lncRNA. The biological function of lncRNA SLC25A21‐AS1 in ESCC was investigated both in vivo and in vitro. Chromatin immunoprecipitation(ChIP)assay, RNA‐pull down, mass spectrometry, co‐IP, and RNA IP(RIP) were performed to explore the molecular mechanism. Finally, an ESCC cDNA microarray was used to determine the clinical prognostic value of SLC25A21‐AS1 by RT‐qPCR. Results Palmitic acid (PA) is an important fatty acid component of HFD and had an inhibitory effect on ESCC cell lines. LncRNA SLC25A21‐AS1 expression was downregulated by PA and associated with the proliferation and migration of ESCC cells in vitro and in vivo. Mechanistically, SLC25A21‐AS1 interacted with nucleophosmin‐1 (NPM1) protein to promote the downstream gene transcription of the c‐Myc in the nucleus. In the cytoplasm, SLC25A21‐AS1 maintained the stability of SLC25A21 mRNA and reduced the intracellular NAD+/NADH ratio by influencing tryptophan catabolism. Finally, we demonstrated that high expression of SLC25A21‐AS1 promoted resistance to cisplatin‐induced apoptosis and was correlated with poor tumour grade and overall survival. Conclusions HFD/PA has an inhibitory effect on ESCC cells and SLC25A21‐AS1 expression. SLC25A21‐AS1 promotes the proliferation and migration of ESCC cells by regulating the NPM1/c‐Myc axis and SLC25A21 expression. In addition, lncRNA SLC25A21‐AS1 may serve as a favourable prognostic biomarker and a potential therapeutic target for ESCC.

Epigenetic modifications in obesity‐associated diseases

“…LncRNAs play a crucial role in predicting the prognosis of obesity‐associated esophageal squamous cell carcinoma (ESCC) 127 . Specifically, the lncRNA SLC25A21‐AS1, associated with lipid metabolism, is recognized as promoting ESCC progression via the nucleophosmin‐1 (NPM1)/c‐Myc signaling pathway 128 . With the in‐depth investigation of genome‐wide association studies in tumor samples, the potential for lncRNAs to function as diagnostic markers and therapeutic targets for cancer has emerged.…”

The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming

“…NcRNAs can also target metabolic pathways related to amino acids to exert regulatory effects. In esophageal squamous cell carcinoma, the increased LncRNA SLC25AS1-AS can not only maintain the stability of SLC25A21 mRNA but also reduce the intracellular NAD + /NADH ratio by affecting tryptophan catabolism [ 148 ]. Ornithine is the initiator of polyamine synthesis, increased expression of polyamine synthesis genes in cancer promotes cancer progression [ 149 ].…”

Histone Chaperones and Digestive Cancer: A Review of the Literature

“…Extensive research has been conducted on the function of NPM1 as a crucial cofactor in c-Myc transforming activity [ 117 ]. In EC and CRC, the NPM1/c-MYC axis promotes cancerous behavior [ 46 , 49 ]. NPM1 also acts as a corepressor or coactivator of transcription by binding to transcription factors.…”